Publications by year
In Press
Curnow A, Anayo L, Magnussen A, Perry A, Wood M (In Press). AN EXPERIMENTAL INVESTIGATION OF a NOVEL IRON CHELATING PROTOPORPHYRIN IX PRODRUG FOR THE ENHANCEMENT OF PHOTODYNAMIC THERAPY. Lasers in Surgery and Medicine
Curnow A, Horton SJ (In Press). An evaluation of root phytochemicals derived from Althea officinalis (Marshmallow) and Astragalus membranaceus as potential natural components of UV-protecting dermatological formulations.
Oxidative Medicine and Cellular LongevityAbstract:
An evaluation of root phytochemicals derived from Althea officinalis (Marshmallow) and Astragalus membranaceus as potential natural components of UV-protecting dermatological formulations
As lifetime exposure to ultraviolet (UV) radiation has risen, the deleterious effects have also become more apparent. Numerous sunscreen and skincare products have therefore been developed to help reduce the occurrence of sunburn, photo-ageing and skin carcinogenesis. This has stimulated research into identifying new natural sources of effective skin protecting compounds. Alkaline single cell gel electrophoresis (comet assay) was employed to assess aqueous extracts derived from soil or hydroponically glasshouse-grown roots of Althea officinalis (Marshmallow) and Astragalus membranaceus, compared with commercial, field-grown roots. Hydroponically grown root extracts from both plant species were found to significantly reduce UVA-induced DNA damage in cultured human lung and skin fibroblasts, although initial Astragalus experimentation detected some genotoxic effects, indicating that Althea root extracts may be better suited as potential constituents of dermatological formulations. Glasshouse-grown soil and hydroponic Althea root extracts afforded lung fibroblasts with statistically significant protection against UVA irradiation for a greater period of time than the commercial field-grown roots. No significant reduction in DNA damage was observed when total ultraviolet irradiation (including UVB) was employed (data not shown), indicating that the extracted phytochemicals predominantly protected against indirect UVA-induced oxidative stress. Althea phytochemical root extracts may therefore be useful components in dermatological formulations.
Abstract.
Curnow A (In Press). Novel iron chelating prodrug (AP2-18) for protoporphyrin IX-induced photodynamic therapy.
Abstract:
Novel iron chelating prodrug (AP2-18) for protoporphyrin IX-induced photodynamic therapy
A novel pharmaceutical compound for use in photodynamic therapy (PDT) has been synthesised (AP2-18; C14H22Cl2N2O5). It includes both iron chelating properties and a protoporphyrin IX (PPIX)-inducing prodrug in a single compound. Efficacy has been demonstrated in vitro in a number of normal and malignant human cell types and is significantly better than the results currently achieved with standard PDT PPIX-prodrugs and separately administered iron chelating agents. This intellectual property therefore has commercial value and the potential to improve patient care in the future (particularly in the treatment of non-melanoma skin cancer).
Abstract.
2021
Curnow A, Magnussen A, Reburn C, Perry A, Wood M (2021). Experimental investigation of a combinational iron chelating. protoporphyrin IX prodrug for fluorescence detection and photodynamic therapy. Lasers in Medical Science
Potiszil K (2021). The Use of Acellular Dermal Matrices in Breast Reconstruction.
Abstract:
The Use of Acellular Dermal Matrices in Breast Reconstruction
Introduction
The use of the Acellular Dermal matrix (ADM) has become widespread in implant based breast reconstruction, with new methods and applications being found each year. Evaluation of complications, cost and outcomes often contrast and are not always applicable to the UK based population. The aim of this thesis is to investigate the safety and cost impact of ADM in patients undergoing breast reconstruction compared to alternate surgical methods.
Methods
A combined retrospective and prospective sample of 337 patients undergoing breast reconstruction was gathered from a single centre from 2010 to 2015. Patient and surgical variables, clinical outcomes and complications were compared between the 126 unilateral ADM-implant, 72 bilateral ADM-implant, 56 Lower Pole Sling (LPS) and 83 Latissimus Dorsi (LD) breast reconstructions. Statistical methods included regression analysis, Poisson regression, and logistic and multinomial logistic regression. Cost of initial surgery and total cost of surgical treatment were compared between the unilateral ADM-implant and LD reconstruction groups using regression analysis.
Results
There was no association of increased complications in patients that received ADM and no significant difference in health economic analysis between the unilateral and LD groups. While patients who received an LD were at increased of donor site complications, these had little downstream impact on further surgery and no impact on cost. The LD reconstruction group was more robust in situations of radiotherapy, smoking and use of Aromatase inhibitors (AI), which were associated with increased complications in patients receiving implant based reconstructions. The use of implants over 600cc was an independent risk factor for complication.
Conclusions
This single centre study adds to evidence that there is no increased risk of complication when using ADM in breast reconstruction. It also demonstrates that implant based breast reconstructions may be less robust than the LD method in certain situations, with no difference in cost. These findings have an important implication for decisions regarding treatment pathways and have been used to produce a decision making aid for the patient and surgeon which considers a variety of variables and odds ratios. It indicates that in the situation of smoking, AI use, radiotherapy, and large volume breasts, the LD reconstruction is a more suitable form of reconstruction in the eligible patient.
Abstract.
2019
Reburn C, Anayo L, Magnussen A, Perry A, Wood M, Curnow A (2019). Experimental findings utilising a new iron chelating ALA prodrug to enhance protoporphyrin IX-induced photodynamic therapy.
Abstract:
Experimental findings utilising a new iron chelating ALA prodrug to enhance protoporphyrin IX-induced photodynamic therapy
Abstract.
Curnow A, Perry A, Wood M (2019). Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug.
Photodiagnosis Photodyn Ther,
25, 157-165.
Abstract:
Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug.
BACKGROUND: Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of cancers and precancers. It is particularly useful in its topical form in dermatology but improvement of efficacy is required to widen its application. METHODS: an ester between aminolaevulinic acid (ALA) and CP94 was synthesised (AP2-18) and experimentally evaluated to determine whether protoporphyrin IX (PpIX)-induced PDT effectiveness could be improved. A biological evaluation of AP2-18 was conducted in cultured human primary cells with both PpIX fluorescence and cell viability (as determined via the neutral red assay) being assessed in comparison to the PpIX prodrugs normally utilised in clinical practice (aminolaevulinic acid (ALA) or its methyl ester (MAL)) either administered alone or with the comparator iron chelator, CP94. RESULTS: No significant dark toxicity was observed in human lung fibroblasts but AP2-18 significantly increased PpIX accumulation above and beyond that achieved with ALA or MAL administration +/- CP94 in both human dermal fibroblasts and epithelial squamous carcinoma cells. On light exposure, the combined hydroxypyridinone iron chelating ALA prodrug AP2-18 generated significantly greater cytotoxicity than any of the other treatment parameters investigated when the lowest concentration (250 μM) was employed. CONCLUSIONS: Newly synthesised AP2-18 is therefore concluded to be an efficacious prodrug for PpIX-induced PDT in these dermatologically relevant human cells, achieving enhanced effects at lower concentrations than currently possible with existing pharmaceuticals.
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Author URL.
Tyrrell J, Paterson C, Curnow A (2019). Insights gained from regression analysis of PpIX fluorescence imaging undertaken during routine dermatological photodynamic therapy.
Abstract:
Insights gained from regression analysis of PpIX fluorescence imaging undertaken during routine dermatological photodynamic therapy
Abstract.
Jeynes JCG, Wordingham F, Moran LJ, Curnow A, Harries TJ (2019). Monte Carlo Simulations of Heat Deposition During Photothermal Skin Cancer Therapy Using Nanoparticles.
Biomolecules,
9(8).
Abstract:
Monte Carlo Simulations of Heat Deposition During Photothermal Skin Cancer Therapy Using Nanoparticles.
Photothermal therapy using nanoparticles is a promising new approach for the treatment of cancer. The principle is to utilise plasmonic nanoparticle light interaction for efficient heat conversion. However, there are many hurdles to overcome before it can be accepted in clinical practice. One issue is a current poor characterization of the thermal dose that is distributed over the tumour region and the surrounding normal tissue. Here, we use Monte Carlo simulations of photon radiative transfer through tissue and subsequent heat diffusion calculations, to model the spatial thermal dose in a skin cancer model. We validate our heat rise simulations against experimental data from the literature and estimate the concentration of nanorods in the tumor that are associated with the heat rise. We use the cumulative equivalent minutes at 43 °C (CEM43) metric to analyse the percentage cell kill across the tumour and the surrounding normal tissue. Overall, we show that computer simulations of photothermal therapy are an invaluable tool to fully characterize thermal dose within tumour and normal tissue.
Abstract.
Author URL.
Tyrrell J, Paterson C, Curnow A (2019). Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy.
Cancers (Basel),
11(1).
Abstract:
Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy.
Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of dermatological cancers and precancers. Improvement of efficacy is required to widen its application. Clinical protoporphyrin IX (PpIX) fluorescence data were obtained using a pre-validated, non-invasive imaging system during routine methyl aminolevulinate (MAL)-PDT treatment of 172 patients with licensed dermatological indications (37.2% actinic keratosis, 27.3% superficial basal cell carcinoma and 35.5% Bowen's disease). Linear and logistic regressions were employed to model any relationships between variables that may have affected PpIX accumulation and/or PpIX photobleaching during irradiation and thus clinical outcome at three months. Patient age was found to be associated with lower PpIX accumulation/photobleaching, however only a reduction in PpIX photobleaching appeared to consistently adversely affect treatment efficacy. Clinical clearance was reduced in lesions located on the limbs, hands and feet with lower PpIX accumulation and subsequent photobleaching adversely affecting the outcome achieved. If air cooling pain relief was employed during light irradiation, PpIX photobleaching was lower and this resulted in an approximate three-fold reduction in the likelihood of achieving clinical clearance. PpIX photobleaching during the first treatment was concluded to be an excellent predictor of clinical outcome across all lesion types.
Abstract.
Author URL.
Curnow A, Tyrrell J, Paterson C (2019). Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy.
Abstract:
Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy.
Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of dermatological cancers and precancers. Improvement of efficacy is required to widen its application. Clinical protoporphyrin IX (PpIX) fluorescence data were obtained using a pre-validated, non-invasive imaging system during routine methyl aminolevulinate (MAL)-PDT treatment of 172 patients with licensed dermatological indications (37.2% actinic keratosis, 27.3% superficial basal cell carcinoma and 35.5% Bowen’s disease). Linear and logistic regressions were employed to model any relationships between variables that may have affected PpIX accumulation and/or PpIX photobleaching during irradiation and thus clinical outcome at three months. Patient age was found to be associated with lower PpIX accumulation/photobleaching, however only a reduction in PpIX photobleaching appeared to consistently adversely affect treatment efficacy. Clinical clearance was reduced in lesions located on the limbs, hands and feet with lower PpIX accumulation and subsequent photobleaching adversely affecting the outcome achieved. If air cooling pain relief was employed during light irradiation, PpIX photobleaching was lower and this resulted in an approximate three-fold reduction in the likelihood of achieving clinical clearance. PpIX photobleaching during the first treatment was concluded to be an excellent predictor of clinical outcome across all lesion types.
Abstract.
2018
Ferguson DCJ, Smerdon GR, Harries LW, Dodd NJF, Murphy MP, Curnow A, Winyard PG (2018). Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia.
Free Radic Biol Med,
126, 322-333.
Abstract:
Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia.
In vivo, mammalian cells reside in an environment of 0.5-10% O2 (depending on the tissue location within the body), whilst standard in vitro cell culture is carried out under room air. Little is known about the effects of this hyperoxic environment on treatment-induced oxidative stress, relative to a physiological oxygen environment. In the present study we investigated the effects of long-term culture under hyperoxia (air) on photodynamic treatment. Upon photodynamic irradiation, cells which had been cultured long-term under hyperoxia generated higher concentrations of mitochondrial reactive oxygen species, compared with cells in a physioxic (2% O2) environment. However, there was no significant difference in viability between hyperoxic and physioxic cells. The expression of genes encoding key redox homeostasis proteins and the activity of key antioxidant enzymes was significantly higher after the long-term culture of hyperoxic cells compared with physioxic cells. The induction of antioxidant genes and increased antioxidant enzyme activity appear to contribute to the development of a phenotype that is resistant to oxidative stress-induced cellular damage and death when using standard cell culture conditions. The results from experiments using selective inhibitors suggested that the thioredoxin antioxidant system contributes to this phenotype. To avoid artefactual results, in vitro cellular responses should be studied in mammalian cells that have been cultured under physioxia. This investigation provides new insights into the effects of physioxic cell culture on a model of a clinically relevant photodynamic treatment and the associated cellular pathways.
Abstract.
Author URL.
Yeo NL, White MP, Ronan N, Whinney DJ, Curnow A, Tyrrell J (2018). Stress and Unusual Events Exacerbate Symptoms in Menière's Disease: a Longitudinal Study.
Otol Neurotol,
39(1), 73-81.
Abstract:
Stress and Unusual Events Exacerbate Symptoms in Menière's Disease: a Longitudinal Study.
HYPOTHESIS: Stress and unusual events are associated with a higher likelihood of attacks and increased symptom severity in Menière's disease (MD). BACKGROUND: MD is an unpredictable condition which severely impacts the quality of life of those affected. It is thought that unusual activity and stress may act as an attack trigger in MD, but research in this area has been limited to date. METHODS: This was a longitudinal study conducted over two phases. A mobile phone application was used to collect daily data on Menière's attacks and individual symptoms (aural fullness, dizziness, hearing loss, and tinnitus), as well as prevalence of unusual events (phase I), and stress levels (phase II). There were 1,031 participants (730 women, mean age 46.0 yr) in phase I and 695 participants (484 women, mean age 47.7 yr) in phase II. Panel data regression analyses were employed to examine for associations between unusual events/stress and attacks/symptoms, including the study of 24 hours lead and lag effects. RESULTS: Unusual events and higher stress levels were associated with higher odds of Menière's attacks and more severe symptoms. The odds of experiencing an attack were 2.94 (95% confidence interval [CI] 2.37, 3.65) with reporting of unusual events and increased by 1.24 (95% CI 1.20, 1.28) per unit increase in stress level. Twenty-four hour lead (OR 1.10 [95% CI 1.07, 1.14]) and lag (OR 1.10 [95% CI 1.06, 1.13]) effects on attacks were also found with increases in stress. CONCLUSION: This study provides the strongest evidence to date that stress and unusual events are associated with attacks and symptom exacerbation in MD. Improving our understanding of stress and unusual events as triggers in Menière's may reduce the uncertainty associated with this condition and lead to improved quality of life for affected individuals.
Abstract.
Author URL.
2017
Curnow A, Buxton C, Tyrrell J (2017). Mechanistic insights gained through regression analysis of PpIX accumulation and photobleaching during dermatological MAL-PDT. Photodiagnosis and Photodynamic Therapy, 17
2016
Dogra Y, Ferguson DCJ, Dodd NJF, Smerdon GR, Curnow A, Winyard PG (2016). The hydroxypyridinone iron chelator CP94 increases methyl-aminolevulinate-based photodynamic cell killing by increasing the generation of reactive oxygen species.
Redox Biol,
9, 90-99.
Abstract:
The hydroxypyridinone iron chelator CP94 increases methyl-aminolevulinate-based photodynamic cell killing by increasing the generation of reactive oxygen species.
Methyl-aminolevulinate-based photodynamic therapy (MAL-PDT) is utilised clinically for the treatment of non-melanoma skin cancers and pre-cancers and the hydroxypyridinone iron chelator, CP94, has successfully been demonstrated to increase MAL-PDT efficacy in an initial clinical pilot study. However, the biochemical and photochemical processes leading to CP94-enhanced photodynamic cell death, beyond the well-documented increases in accumulation of the photosensitiser protoporphyrin IX (PpIX), have not yet been fully elucidated. This investigation demonstrated that MAL-based photodynamic cell killing of cultured human squamous carcinoma cells (A431) occurred in a predominantly necrotic manner following the generation of singlet oxygen and ROS. Augmenting MAL-based photodynamic cell killing with CP94 co-treatment resulted in increased PpIX accumulation, MitoSOX-detectable ROS generation (probably of mitochondrial origin) and necrotic cell death, but did not affect singlet oxygen generation. We also report (to our knowledge, for the first time) the detection of intracellular PpIX-generated singlet oxygen in whole cells via electron paramagnetic resonance spectroscopy in conjunction with a spin trap.
Abstract.
Author URL.
2015
Curnow A, MacRobert AJ, Bown SG (2015). Enhancing Protoporphyrin IX-induced Photodynamic Therapy with a Topical Iron Chelating Agent in a Normal Skin Model.
Journal of Heavy Metal Toxicity and Diseases,
1(1), 1-9.
Abstract:
Enhancing Protoporphyrin IX-induced Photodynamic Therapy with a Topical Iron Chelating Agent in a Normal Skin Model
Protoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being utilised within dermatological practice as a topical method of localised ablation of non-melanoma skin cancer/precancer. Standardised protocols have been implemented to good effect when the disease remains superficial but improvement is required to widen the application of this light activated drug therapy to treat thicker or acrally located conditions. As innate haem biosynthesis is exploited to accumulate the light sensitive PpIX from a topically applied inert prodrug (aminolaevulinic acid; ALA), this pathway can be further manipulated through the concurrent administration of an iron chelating agent to hyper-accumulate PpIX by temporarily reducing its iron dependent conversion to haem.
A topical preparation of ALA was applied to normal rat skin with or without the hydroxypyridinone iron chelator, CP94. Image analysis quantification of tissue fluorescence following excision indicated that ALA plus CP94 produced 29.0% more fluorescence than ALA alone (p < 0.09), peaking at 5 hours. Furthermore, fluorescence spectroscopy of frozen skin samples from each treatment group were characteristic of PpIX (maxima 636 +/- 2 nm), indicating that topical CP94 administration elevated PpIX levels without significantly producing any other fluorescent species. When PDT efficacy was considered post irradiation, a substantial three-fold increase in effect was observed 4 days after treatment when the iron chelator CP94 was co-administered topically with the prodrug (p < 0.07).
It has therefore been established that the hydroxypyridinone CP94, is topically active within normal rat skin, effectively chelating iron to elevate PpIX accumulation and thus improve PDT efficacy.
Abstract.
Curnow A, Pye A (2015). The importance of iron chelation and iron availability during PpIX-induced photodynamic therapy.
Photonics and Lasers in Medicine,
4(1), 39-58.
Abstract:
The importance of iron chelation and iron availability during PpIX-induced photodynamic therapy
Background: Protoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being utilised as a topical method of localised ablation of certain non-melanoma skin cancers and precancers. Standardised protocols have been implemented to good effect when the disease remains superficial but improvement is required to treat thicker or acrally located conditions. Concurrent administration of an iron chelator during PpIX-PDT has been demonstrated to increase cellular accumulation of PpIX by reducing its bioconversion to haem (an iron dependent process) thus increasing cell kill on subsequent irradiation. Iron however, can also play a role in reactive oxygen species (ROS) generation and limiting its availability via chemical chelation could theoretically reduce the efficacy of PpIX-PDT, so that a response less than that maximally feasible is produced. Materials and methods: the effects of iron availability and chelation on PpIX-PDT have therefore been investigated via fluorescence quantification of PpIX accumulation, single-cell gel electrophoresis (comet assay) measurement of ROS-induced DNA damage and trypan blue exclusion assessment of cell viability. Cultured human cells were utilised and incubated in standardised iron conditions with the PpIX precursor's aminolaevulinic acid (ALA) or its methyl ester (MAL) in the presence or absence of either of the iron chelating agents desferrioxamine (DFO) or hydroxypyridinone (CP94), or alternatively iron sulphate as a source of iron. Results: ALA or MAL incubation was found to significantly increase cellular PpIX accumulation pre-irradiation as anticipated and this observation correlated with both significantly increased DNA damage and reduced cellular viability following irradiation. Co-incubation with either of the iron chelators investigated (DFO or CP94) significantly increased pre-irradiation PpIX accumulation as well as DNA damage and cell death on irradiation indicating the positive effect of iron chelation on the effectiveness of PpIX-induced PDT. The opposite effects were observed however, when the cells were co-incubated with iron sulphate, with significant reductions in pre-irradiation PpIX accumulation (ALA only) and DNA damage (ALA and MAL) being recorded indicating the negative effects excessive iron can have on PpIX-PDT effectiveness. Some dark toxicity produced by iron sulphate administration in non-irradiated control groups was also observed. Conclusion: Iron chelation and availability have therefore been observed to positively and adversely affect the PpIX-PDT process respectively and it is concluded that the effects of increased PpIX accumulation pre-irradiation produced via iron chelation outweigh any limitations reduced iron availability may have on the ability of iron to catalyse ROS generation/cascades following PpIX-induced PDT. Further investigation of iron chelation within dermatological applications where enhanced PpIX-PDT treatment effects would be beneficial is therefore warranted.
Abstract.
Curnow A, Tyrrell J (2015). The mechanism of action of topical dermatological photodynamic therapy. In (Ed)
Photodynamic Therapy: Fundamentals, Applications and Health Outcomes, 59-102.
Abstract:
The mechanism of action of topical dermatological photodynamic therapy
Abstract.
2013
Blake E, Allen J, Thorn C, Shore A, Curnow A (2013). Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy.
Lasers in Medical Science,
28(3), 997-1005.
Abstract:
Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy
Methyl aminolevulinate photodynamic therapy (MAL-PDT) (a topical treatment used for a number of precancerous skin conditions) utilizes the combined interaction of a photosensitizer (protoporphyrin IX (PpIX)), light of the appropriate wavelength, and molecular oxygen to produce singlet oxygen and other reactive oxygen species which induce cell death. During treatment, localized oxygen depletion occurs and is thought to contribute to decreased efficacy. The aim of this study was to investigate whether an oxygen pressure injection (OPI) device had an effect on localized oxygen saturation levels and/or PpIX fluorescence of skin lesions during MAL-PDT. This study employed an OPI device to apply oxygen under pressure to the skin lesions of patients undergoing standard MAL-PDT. Optical reflectance spectrometry and fluorescence imaging were used to noninvasively monitor the localized oxygen saturation and PpIX fluorescence of the treatment area, respectively. No significant changes in oxygen saturation were observed when these data were combined for the group with OPI and compared to the group that received standard MAL-PDT without OPI. Additionally, no significant difference in PpIX photobleaching or clinical outcome at 3 months between the groups of patients was observed, although the group that received standard MAL-PDT demonstrated a significant increase (p < 0.05) in PpIX fluorescence initially and both groups produced a significant decrease (p < 0.05) after light irradiation. In conclusion, with this sample size, this OPI device was not found to be an effective method with which to improve tissue oxygenation during MAL-PDT. Further investigation is therefore required to find a more effective method of MAL-PDT enhancement. © 2012 Springer-Verlag London Ltd.
Abstract.
Robertson A, Allen J, Laney R, Curnow A (2013). The cellular and molecular carcinogenic effects of radon exposure: a review.
Int J Mol Sci,
14(7), 14024-14063.
Abstract:
The cellular and molecular carcinogenic effects of radon exposure: a review.
Radon-222 is a naturally occurring radioactive gas that is responsible for approximately half of the human annual background radiation exposure globally. Chronic exposure to radon and its decay products is estimated to be the second leading cause of lung cancer behind smoking, and links to other forms of neoplasms have been postulated. Ionizing radiation emitted during the radioactive decay of radon and its progeny can induce a variety of cytogenetic effects that can be biologically damaging and result in an increased risk of carcinogenesis. Suggested effects produced as a result of alpha particle exposure from radon include mutations, chromosome aberrations, generation of reactive oxygen species, modification of the cell cycle, up or down regulation of cytokines and the increased production of proteins associated with cell-cycle regulation and carcinogenesis. A number of potential biomarkers of exposure, including translocations at codon 249 of TP53 in addition to HPRT mutations, have been suggested although, in conclusion, the evidence for such hotspots is insufficient. There is also substantial evidence of bystander effects, which may provide complications when calculating risk estimates as a result of exposure, particularly at low doses where cellular responses often appear to deviate from the linear, no-threshold hypothesis. At low doses, effects may also be dependent on cellular conditions as opposed to dose. The cellular and molecular carcinogenic effects of radon exposure have been observed to be both numerous and complex and the elevated chronic exposure of man may therefore pose a significant public health risk that may extend beyond the association with lung carcinogenesis.
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Author URL.
Blake E, Allen J, Curnow A (2013). The effects of protoporphyrin IX-induced photodynamic therapy with and without iron chelation on human squamous carcinoma cells cultured under normoxic, hypoxic and hyperoxic conditions.
Photodiagnosis and Photodynamic Therapy,
10(4), 575-582.
Abstract:
The effects of protoporphyrin IX-induced photodynamic therapy with and without iron chelation on human squamous carcinoma cells cultured under normoxic, hypoxic and hyperoxic conditions
Background: Photodynamic therapy requires the combined interaction of a photosensitiser, light and oxygen to ablate target tissue. In this study we examined the effect of iron chelation and oxygen environment manipulation on the accumulation of the clinically useful photosensitiser protoporphyrin IX (PpIX) within human squamous epithelial carcinoma cells and the subsequent ablation of these cells on irradiation. Methods: Cells were incubated at concentrations of 5%, 20% or 40% oxygen for 24h prior to and for 3h following the administration of the PpIX precursors aminolevulinic acid (ALA), methyl aminolevulinate (MAL) or hexylaminolevulinate (HAL) with or without the iron chelator 1,2-diethyl-3-hydroxypyridin-4-one hydrochloride (CP94). PpIX accumulation was monitored using a fluorescence plate reader, cells were irradiated with 37J/cm2 red light and cell viability measured using the neutral red uptake assay. Results: Manipulation of the oxygen environment and/or co-administration of CP94 with PpIX precursors resulted in significant changes in both PpIX accumulation and photobleaching. Incubation with 5% or 40% oxygen produced the greatest levels of PpIX and photobleaching in cells incubated with ALA/MAL. Incorporation of CP94 also resulted in significant decreases in cell viability following administration of ALA/MAL/HAL, with oxygen concentration predominantly having a significant effect in cells incubated with HAL. Conclusions: Experimentation with human squamous epithelial carcinoma cells has indicated that the iron chelator CP94 significantly increased PpIX accumulation induced by each PpIX congener investigated (ALA/MAL/HAL) at all oxygen concentrations employed (5%/20%/40%) resulting in increased levels of photobleaching and reduced cell viability on irradiation. Further detailed investigation of the complex relationship of PDT cytotoxicity at various oxygen concentrations is required. It is therefore concluded that iron chelation with CP94 is a simple protocol modification with which it may be much easier to enhance clinical PDT efficacy than the complex and less well understood process of oxygen manipulation. © 2013.
Abstract.
2012
Ferguson D, Smerdon GR, Eggleton P, Curnow A, Winyard PG (2012). Altering oxygen concentrations to enhance the efficacy of PpIX-based photodynamic cell killing.
FREE RADICAL BIOLOGY AND MEDICINE,
53, S127-S127.
Author URL.
Ferguson D, Smerdon GR, Eggleton P, Curnow A, Winyard PG (2012). Altering oxygen concentrations to enhance the efficacy of PpIX-based photodynamic cell killing.
Wheeler BW, Allen J, Depledge MH, Curnow A (2012). Radon and skin cancer in southwest England: an ecologic study.
Epidemiology,
23(1), 44-52.
Abstract:
Radon and skin cancer in southwest England: an ecologic study
Background: Radon, a naturally occurring radioactive gas, is a carcinogen that causes a small proportion of lung cancers among exposed populations. Theoretical models suggest that radon may also be a risk factor for skin cancer, but epidemiologic evidence for this relationship is weak. In this study, we investigated ecologic associations between environmental radon concentration and the incidence of various types of skin cancer. Methods: We analyzed data for 287 small areas (postcode sectors) in southwest England for the years 2000-2004. Poisson regression was used to compare registration rates of malignant melanoma, basal cell carcinoma, and squamous cell carcinoma across mean indoor radon concentrations from household surveys. Analyses were adjusted for potentially confounding factors, including age, sex, population socioeconomic status, and mean hours of bright sunshine. Results: No association was observed between mean postcode sector radon concentration and either malignant melanoma or basal cell carcinoma registration rates. However, sectors with higher radon levels had higher squamous cell carcinoma registration rates, with evidence of an exposure-response relationship. Comparing highest and lowest radon categories, postcode sectors with mean radon ≥230 Bq/m 3 had registration rates 1.76 (95% confidence interval=1.46-2.11) times those with mean radon 0-39 Bq/m 3. Associations persisted after adjustment for potential confounders. Conclusions: This ecologic study suggests that environmental radon exposure may be a risk factor for squamous cell carcinoma. Further study is warranted to overcome ecologic design limitations and to determine whether this relationship is generalizable to national and international settings. © 2011 by Lippincott Williams & Wilkins.
Abstract.
Blake E, Campbell S, Allen J, Mathew J, Helliwell P, Curnow A (2012). The time-dependent accumulation of protoporphyrin IX fluorescence in nodular basal cell carcinoma following application of methyl aminolevulinate with an oxygen pressure injection device.
J Photochem Photobiol B,
117, 97-103.
Abstract:
The time-dependent accumulation of protoporphyrin IX fluorescence in nodular basal cell carcinoma following application of methyl aminolevulinate with an oxygen pressure injection device.
Topical protoporphyrin (PpIX)-induced photodynamic therapy (PDT) relies on the penetration of the prodrug into the skin lesion and subsequent accumulation of the photosensitizer. Methyl aminolevulinate (MAL)-PDT is an established treatment for thinner and superficial non-melanoma skin cancers (NMSCs) but for the treatment of the thicker nodular basal cell carcinoma (nBCC) enhanced penetration of the prodrug is required. This study employed a new higher pressure, oxygen pressure injection (OPI) device, at the time of Metvix® application with a view to enhancing the penetration of MAL into the tumors. Each patient had Metvix® applied to a single nBCC followed by application of a higher pressure OPI device. Following different time intervals (0, 30, 60, 120 or 180 min) the tumors were excised. The maximum depth and area of MAL penetration achieved in each lesion was measured using PpIX fluorescence microscopy. As expected, an increase in the depth of MAL-induced PpIX accumulation and area of tumor sensitized was observed over time; when the Metvix® cream was applied for 0, 30, 60, 120 and 180 min the median depth of PpIX fluorescence was 0%, 21%, 26.5%, 75.5% and 90%, respectively and the median area of tumor sensitized was 0%, 4%, 6%, 19% and 60%, respectively. As the investigation presented here did not include a control arm, the relative depths of fluorescence observed in this study were statistically compared (using the non-parametric Mann Whitney U test) with the results of our previous study where patients had Metvix® cream applied either with or without the standard pressure OPI device. When the higher pressure OPI device was employed compared to without OPI this increase was observed to be greater following 30, 120, and 180 min although overall not significantly (p=0.835). In addition, no significant difference between the higher pressure OPI device employed here and the previously investigated standard pressure OPI device was observed (p=0.403). However, when the results for both OPI devices were combined and compared to the standard treatment (no OPI employed) group, although the difference did not reach significance (p=0.531) a consistent and substantial increase in the depth of PpIX fluorescence was observed, therefore employment of an OPI device during topical MAL-PDT protocols warrants further investigation as a technique for enhancing MAL penetration.
Abstract.
Author URL.
2011
Blake E, Allen J, Curnow A (2011). An in vitro comparison of the effects of the iron-chelating agents, CP94 and dexrazoxane, on protoporphyrin IX accumulation for photodynamic therapy and/or fluorescence guided resection.
Photochem Photobiol,
87(6), 1419-1426.
Abstract:
An in vitro comparison of the effects of the iron-chelating agents, CP94 and dexrazoxane, on protoporphyrin IX accumulation for photodynamic therapy and/or fluorescence guided resection.
Photodynamic therapy (PDT) utilizes the combined interaction of a photosensitizer, light and molecular oxygen to ablate tumor tissue. Maximizing the accumulation of the photosensitizer protoporphyrin IX (PpIX) within different cell types would be clinically useful. Dermatological PpIX-induced PDT regimes produce good clinical outcomes but this currently only applies when the lesion remains superficial. Also, as an adjuvant therapy for the treatment of primary brain tumors, fluorescence guided resection (FGR) and PDT can be used to highlight and destroy tumor cells unreachable by surgical resection. By employing iron chelators PpIX accumulation can be enhanced. Two iron-chelating agents, 1,2-diethyl-3-hydroxypyridin-4-one hydrochloride (CP94) and dexrazoxane, were individually combined with the porphyrin precursors aminolevulinic acid (ALA), methyl aminolevulinate (MAL) and hexyl aminolevulinate (HAL). Efficacies of the iron-chelating agents were compared by recording the PpIX fluorescence in human squamous epithelial carcinoma cells (A431) and human glioma cells (U-87 MG) every hour for up to 6 h. Coincubation of ALA/MAL/HAL with CP94 resulted in a greater accumulation of PpIX compared to that produced by coincubation of these congeners with dexrazoxane. Therefore the clinical employment of iron chelation, particularly with CP94 could potentially increase and/or accelerate the accumulation of ALA/MAL/HAL-induced PpIX for PDT or FGR.
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Author URL.
Morris J, Laing-Morton T, Marno P, Curnow A (2011). An investigation into the awareness and understanding of the ultraviolet index forecasts in the South West of England.
Photochem. Photobiol. Sci.Abstract:
An investigation into the awareness and understanding of the ultraviolet index forecasts in the South West of England
Despite large sun protection behaviour intervention campaigns there has not been a marked reduction in the incidence of skin cancer. This study explored the awareness and understanding of global solar UV index (UVI) information presented to the public in weather forecasts and whether individuals changed their sun exposure/protection behaviour as a result of receiving such information. A cross-sectional, face-to-face survey was undertaken in Devon and Cornwall in the South West of England between 20 August and 7 September 2008. 466 interviews were completed; 53% at beach locations and 38% in town centres. The specified targets for the interviews were achieved: males (n = 232), females (n = 234); resident (n = 251), tourist (n = 215); aged 16–34 (n = 156), 35–54 (n = 158), and 55 years plus (n = 152). Sixty-seven percent of participants had heard of the UVI (the predominant source being television broadcasts). Only 40% were able to state correctly that a value of 7 would be considered to be ‘high’. Sixty percent indicated that knowing the UVI value did not influence their sun protection behaviour. Awareness of UVI in the UK appears to have altered little in the past decade and although some improvements in understanding have been observed, it is concerning that this information is not influencing most individual's sun protection behaviour.
Abstract.
Tyrrell JS, Morton C, Campbell SM, Curnow A (2011). Comparison of protoporphyrin IX accumulation and destruction during methylaminolevulinate photodynamic therapy of skin tumours located at acral and nonacral sites.
Br J Dermatol,
164(6), 1362-1368.
Abstract:
Comparison of protoporphyrin IX accumulation and destruction during methylaminolevulinate photodynamic therapy of skin tumours located at acral and nonacral sites.
BACKGROUND: Topical photodynamic therapy (PDT) is successful in the treatment of nonmelanoma skin cancers and associated precancers, but efficacy is significantly reduced in actinic keratosis lesions not located on the face or scalp. OBJECTIVES: to compare the changes in protoporphyrin IX (PpIX) fluorescence in lesions undergoing routine methylaminolevulinate (MAL) PDT and the clinical outcome observed 3 months after treatment in lesions located at acral and nonacral sites. METHODS: This study was a noninterventional, nonrandomized, observational study, which monitored changes in PpIX fluorescence in 200 lesions during standard dermatological MAL-PDT. These data were subsequently analysed in terms of lesions located at acral and nonacral sites. RESULTS: Clinical clearance was significantly reduced (P < 0·01) in acral skin lesions when compared with lesions located at nonacral sites. The accumulation and destruction of PpIX fluorescence was significantly reduced in these acral lesions (P < 0·05 and P < 0·001, respectively). Specifically, lesion location at acral sites significantly reduced changes in PpIX fluorescence in actinic keratosis lesions during MAL-PDT (P < 0·01 and P < 0·05). CONCLUSIONS: These data suggest that reduced PpIX accumulation and the subsequent reduction in PpIX photobleaching within acral lesions result in the reduced responsiveness of these lesions to MAL-PDT. Future work should therefore aim to improve photosensitizer accumulation/photobleaching within lesions located at acral sites.
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Author URL.
Allen J, Tyrrell J, Morton C, Campbell S, Curnow A (2011). Comparison of protoporphyrin IX accumulation and photobleaching during methyl-aminolevulinate photodynamic therapy of skin tumours located at acral and non-acral sites. Photodiagnosis and Photodynamic Therapy, 8(2).
Blake E, Allen J, Curnow A (2011). Maximising protoporphyrin IX (PpIX) accumulation with the hydroxypyridinone iron chelator CP94. Photodiagnosis and Photodynamic Therapy, 8(2), 212-213.
Tyrrell J, Campbell SM, Curnow A (2011). Monitoring the accumulation and dissipation of the photosensitizer protoporphyrin IX during standard dermatological methyl-aminolevulinate photodynamic therapy utilizing non-invasive fluorescence imaging and quantification.
Photodiagnosis Photodyn Ther,
8(1), 30-38.
Abstract:
Monitoring the accumulation and dissipation of the photosensitizer protoporphyrin IX during standard dermatological methyl-aminolevulinate photodynamic therapy utilizing non-invasive fluorescence imaging and quantification.
BACKGROUND: Dermatological methyl-aminolevulinate photodynamic therapy (MAL-PDT) is utilized to successfully treat dermatological conditions. This study monitored fluorescence changes attributed to the accumulation and destruction of the photosensitizer, protoporphyrin IX (PpIX), at several different stages during the first and second treatments of clinical dermatological MAL-PDT. METHODS: a commercially available, non-invasive, fluorescence imaging system (Dyaderm, Biocam, Germany) was utilized to monitor fluorescence changes during the first and second MAL-PDT treatments in seventy-five lesions. RESULTS: the clinical data indicated statistically significant increases in fluorescence within lesions following the application of MAL for both treatments (P
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Curnow A, Tyrrell J, Campbell S (2011). Non-invasive monitoring of dermatological PDT. Photodiagnosis and Photodynamic Therapy, 8(2), 144-145.
Tyrrell J, Thorn C, Shore A, Campbell S, Curnow A (2011). Oxygen saturation and perfusion changes during dermatological methyl-aminolevulinate photodynamic therapy. British Journal of Dermatology
Tyrrell J, Campbell SM, Curnow A (2011). The effect of air cooling pain relief on protoporphyrin IX photobleaching and clinical efficacy during dermatological photodynamic therapy.
J Photochem Photobiol B,
103(1), 1-7.
Abstract:
The effect of air cooling pain relief on protoporphyrin IX photobleaching and clinical efficacy during dermatological photodynamic therapy.
Methyl aminolevulinate photodynamic therapy (MAL-PDT) is utilized to successfully treat licensed indications (e.g. actinic keratosis (AK), superficial basal cell carcinoma (sBCC) and Bowen's disease (BD)) in the UK. Air cooling devices (ACD) are commonly utilized as a method of pain relief, however the effect of this on treatment outcome has never been extensively investigated. This non-randomized, retrospective observational controlled study investigated whether the application of the ACD limited photosensitiser (protoporphyrin IX - PpIX) photobleaching during irradiation and/or subsequent clinical outcome. Patients utilizing the ACD throughout treatment were observed to undergo significantly less PpIX photobleaching than the control group (P
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2010
Curnow A, Campbell SM (2010). Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma: further explanation of a dose-escalating pilot study conducted primarily to consider the safety of this pharmacological modification.
Br J Dermatol,
162(1), 224-225.
Author URL.
Campbell SM, Tyrrell J, Marshall R, Curnow A (2010). Effect of MAL-photodynamic therapy on hypertrophic scarring.
Photodiagnosis Photodyn Ther,
7(3), 183-188.
Abstract:
Effect of MAL-photodynamic therapy on hypertrophic scarring.
BACKGROUND: Patients with localised scleroderma receiving aminolevulinic acid (ALA)/methyl aminolevulinic acid (MAL)-photodynamic therapy (PDT) were noted to show a reduction in skin tightness, suggesting that this therapy reduces skin sclerosis. Karrer and colleagues treated patients with 5-ALA-PDT once or twice weekly for 3-6 months and in all patients the therapy was reported to be highly effective for sclerotic plaques. In view of the potential benefit of PDT in reducing skin sclerosis, the following study looks at the possible clinical and histological effects of topical PDT on the mechanism of scarring, looking particularly at hypertrophic scars. METHODS: Patients with long standing hypertrophic scars were treated with MAL-PDT on two occasions at week apart, and repeated for 3 sessions at 6-weekly intervals. PDT effect was studied by means of fluorescence imaging throughout the treatment and biopsies were taken prior to and 6 weeks post-treatment to observe histological changes. RESULTS AND CONCLUSIONS: Six weeks following the treatment the scarred areas had significantly softened and become more flexible clinically and histologically there had been a significant increase in elastin fibres. This suggests that ALA/MAL-PDT may be a useful treatment or adjuvant therapy in the treatment of scarring.
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Wilkinson C, Saunders M, Curnow A (2010). Measures of ultraviolet radiation in the South West.
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Tyrrell J, Campbell S, Curnow A (2010). Protoporphyrin IX photobleaching during the light irradiation phase of standard dermatological methyl-aminolevulinate photodynamic therapy.
Photodiagnosis Photodyn Ther,
7(4), 232-238.
Abstract:
Protoporphyrin IX photobleaching during the light irradiation phase of standard dermatological methyl-aminolevulinate photodynamic therapy.
BACKGROUND: Methyl-aminolevulinate photodynamic therapy (MAL-PDT) is a successful treatment for non-melanoma skin cancers in the UK. Monitoring the photobleaching of the photosensitiser, protoporphyrin IX (PpIX) during treatment has been demonstrated to indicate the efficacy of the treatment. This study investigated photobleaching during light irradiation. METHODS: a validated non-invasive fluorescence imaging system was utilised to monitor changes in PpIX fluorescence during light irradiation. Fifty patients were recruited to this study, with patients monitored before, during (forty patients at the half way stage and ten at regular intervals in the initial phase of treatment) and after light irradiation. RESULTS: Phased PpIX photobleaching was observed during light irradiation with a significantly greater change (P
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Blake E, Curnow A (2010). The hydroxypyridinone iron chelator CP94 can enhance PpIX-induced PDT of cultured human glioma cells.
Photochem Photobiol,
86(5), 1154-1160.
Abstract:
The hydroxypyridinone iron chelator CP94 can enhance PpIX-induced PDT of cultured human glioma cells.
Photodynamic therapy (PDT) with the pro-drugs 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) utilizes the combined interaction of a photosensitizer, light and molecular oxygen to ablate tumor tissue. To potentially increase accumulation of the photosensitizer, protoporphyrin IX (PpIX), within tumor cells an iron chelator can be employed. This study analyzed the effects of ALA/MAL-induced PDT combined with the iron chelator 1, 2-diethyl-3-hydroxypyridin-4-one hydrochloride (CP94) on the accumulation of PpIX in human glioma cells in vitro. Cells were incubated for 0, 3 and 6h with various concentrations of ALA/MAL with or without CP94 and the resulting accumulations of PpIX, which naturally fluoresces, were quantified prior to and following light irradiation. In addition, counts of viable cells were recorded. The use of CP94 in combination with ALA/MAL produced significant enhancements of PpIX fluorescence in human glioma cells. At the highest concentrations of each prodrug, CP94 enhanced PpIX fluorescence significantly at 3h for ALA and by more than 50% at 6h for MAL. Cells subsequently treated with ALA/MAL-induced PDT in combination with CP94 produced the greatest cytotoxicity. It is therefore concluded that with further study CP94 may be a useful adjuvant to photodiagnosis and/or PpIX-induced PDT treatment of glioma.
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Tyrrell JS, Campbell SM, Curnow A (2010). The relationship between protoporphyrin IX photobleaching during real-time dermatological methyl-aminolevulinate photodynamic therapy (MAL-PDT) and subsequent clinical outcome.
Lasers Surg Med,
42(7), 613-619.
Abstract:
The relationship between protoporphyrin IX photobleaching during real-time dermatological methyl-aminolevulinate photodynamic therapy (MAL-PDT) and subsequent clinical outcome.
BACKGROUND AND OBJECTIVE: the relationship between protoporphyrin IX (PpIX) photobleaching and cellular damage during aminolevulinic (ALA) photodynamic therapy (PDT) has been studied at the cellular level. This study assessed the capability of a non-invasive fluorescence imaging system (Dyaderm, Biocam, Germany), to monitor changes in PpIX during real time methyl-aminolevulinate (MAL) PDT in dermatological lesions, and thus to act as a predictive tool in terms of observed clinical outcome post-treatment. MATERIALS AND METHODS: Patients attending Royal Cornwall Hospital (Truro, UK) for MAL-PDT to licensed lesions (actinic keratosis, Bowen's disease, and basal cell carcinoma) were monitored using the pre-validated non-invasive fluorescence imaging system. Patients were imaged at three distinct time points: prior to the application of MAL, after the 3 hours of MAL application and immediately following light irradiation. The fluorescence intensity of the images were analysed with image analysis software and the percentage change in fluorescence during light irradiation was related to the clinical outcome observed 3 months following treatment. In total 100 patients underwent at least one session of MAL-PDT. RESULTS: Significantly higher levels of change in PpIX fluorescence during light irradiation (P0.500) was observed in the total levels of PpIX recorded after MAL application in patients undergoing partial and complete clearance at 3 months. CONCLUSIONS: PpIX photobleaching is indicative of the level of cellular damage PDT treatment will induce and therefore the clinical outcome expected within patients. This study indicated the potential of the commercially available fluorescence imaging system investigated to predict treatment success at the time of light irradiation and in the future it may be possible to employ it to individualise treatment parameters to improve dermatological PDT efficacy/outcome.
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Malhomme de la Roche H, Seagrove S, Mehta A, Divekar P, Campbell S, Curnow A (2010). Using natural dietary sources of antioxidants to protect against ultraviolet and visible radiation-induced DNA damage: an investigation of human green tea ingestion.
J Photochem Photobiol B,
101(2), 169-173.
Abstract:
Using natural dietary sources of antioxidants to protect against ultraviolet and visible radiation-induced DNA damage: an investigation of human green tea ingestion.
Oral ingestion of green tea is a potent dietary source of antioxidant polyphenols. These compounds are of interest as they may be able to provide additional protection to the body to help prevent the deleterious effects of ultraviolet a and visible radiation (UVA/VIS) produced indirectly via reactive oxygen species (ROS) in sunlight exposed skin. A small clinical study was conducted in ten healthy adult volunteers. Samples of whole blood were obtained from each before and 30, 60 and 90 min following ingestion of three breakfast cups of green tea (540 ml in total) prepared in a standardised manner. Peripheral leucocytes were isolated from each blood sample and exposed to increasing periods of UVA/VIS irradiation in the laboratory (0, 9, 12 or 18 min). Alkaline single cell gel electrophoresis (the comet assay) was then conducted to determine the level of DNA damage in each sample from each individual. The findings support those of our previous pilot study and indicate that drinking green tea did significantly reduce the genotoxic effects observed in peripheral blood cells 60 min following ingestion when artificially exposed to 12 min of UVA/VIS irradiation in the laboratory. It is postulated that this protection is afforded by the polyphenol compounds (known to be contained within green tea) via scavenging or quenching of the damaging ROS induced by this form of light exposure. Further investigation should consider whether this dietary-induced protection could be extended to cells of the skin.
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Tyrrell J, Campbell S, Curnow A (2010). Validation of a non-invasive fluorescence imaging system to monitor dermatological PDT.
Photodiagnosis Photodyn Ther,
7(2), 86-97.
Abstract:
Validation of a non-invasive fluorescence imaging system to monitor dermatological PDT.
BACKGROUND: Methyl-aminolevulinate (MAL) photodynamic therapy (PDT) involves selective accumulation of a photosensitiser, protoporphyrin IX (PpIX), primarily in tumour tissue, which in combination with visible light and tissue oxygen results in reactive oxygen species (ROS) production and thus cellular destruction. METHODS: a non-invasive fluorescence imaging system (Dyaderm, Biocam, Germany) has been employed to acquire colour (morphological) and fluorescent (physiological) images simultaneously during dermatological PDT. This system had been previously utilised for fluorescence diagnosis, however, here changes in PpIX concentration within the skin lesions and normal tissue were followed after MAL application. Measurements were also recorded from a synthetic PpIX standard. RESULTS: Results indicated that imaging distance, imaging angle, position of the region of interest and light conditions all altered the PpIX levels acquired from the synthetic PpIX standard. The imaging system was therefore adapted and a standard operating procedure developed allowing reproducible images of dermatological lesions to be acquired. Different concentrations of synthetic PpIX were analysed with the system and a linear relationship was observed between the PpIX concentration and the mean greyscale value calculated for the images acquired up to 10 microM. CONCLUSIONS: the Dyaderm imaging system can now be used reproducibly with confidence to semi-quantify PpIX (within the range of 0-10 microM) within dermatological lesions using the standard operating procedure derived from this work.
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2009
Curnow A (2009). 12th World Congress of the International Photodynamic Association (IPA), 11-15th June 2009, Seattle, USA.
Photodiagnosis Photodyn Ther,
6(2), 150-151.
Author URL.
Curnow A, Pye A, Campbell S (2009). Enhancing protoporphyrin IX-induced PDT. Photodynamic Therapy - Back to the Future.
Abstract:
Enhancing protoporphyrin IX-induced PDT
Abstract.
Pye A, Dogra Y, Tyrrell J, Winyard P, Curnow A (2009). Photodynamic therapy with aminolaevulinic acid and iron chelators: a clinical example of redox signaling. In Jacob C, Winyard P (Eds.) Redox signaling and regulation in biology and medicine, Weinheim: Wiley-VCH, 381-404.
Pye A, Dogra Y, Tyrrell J, Winyard PG, Curnow A (2009). Photodynamic therapy with aminolevulinic acid and iron chelators: a clinical example of redox signaling. In Jacob C, Winyard PG, Wiley-VCH (Eds.) Redox Signaling and Regulation in Biology and Medicine, Weinheim, Germany: , 351-372.
Tyrrell J, Campbell S, Curnow A (2009). The utilization of a non-invasive fluorescence imaging system to follow clinical dermatological MAL-PDT. Photodynamic Therapy - Back to the Future.
Abstract:
The utilization of a non-invasive fluorescence imaging system to follow clinical dermatological MAL-PDT
Abstract.
Curnow A, Dogra Y, Winyard PG, Campbell S (2009). Using iron chelating agents to enhance dermatological PDT.
2008
McGovern G, Tyrrell J, Campbell S, Curnow A (2008). Audit on the use of photodynamic therapy (PDT) for various malignant and pre-malignant skin conditions. British Association of Dermatology.
Campbell SM, Morton CA, Alyahya R, Horton S, Pye A, Curnow A (2008). Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma.
Br J Dermatol,
159(2), 387-393.
Abstract:
Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma.
BACKGROUND: Photodynamic therapy (PDT) involves the activation of a photosensitizer by visible light to produce activated oxygen species within target cells, resulting in their destruction. Evidence-based guidelines support the efficacy of PDT using topical 5-aminolaevulinic acid (ALA-PDT) in actinic keratoses, Bowen disease and basal cell carcinoma (BCC). Efficacy for nodular BCC appears inferior to that for superficial BCC unless prior debulking or repeat treatments are performed. Objectives the aim of this study was to assess the safety and efficacy of adding a novel iron-chelating agent, CP94 (1,2-diethyl-3-hydroxypyridin-4-one hydrochloride), to topical ALA, to temporarily increase the accumulation of the photosensitizer in the tumour. METHODS: a mixed topical formulation of ALA + increasing concentrations of CP94 was used to carry out PDT on previously biopsied nodular BCC with no prior lesion preparation using standard light delivery. The area was assessed clinically and surgically excised 6 weeks later for histological examination. RESULTS: Enhanced PDT using 40% CP94 resulted in significantly greater clearance rates in nodular BCC than with ALA-PDT alone, in our protocol of single-treatment PDT with no lesion preparation. CONCLUSIONS: the results of this study demonstrate the safe and effective use of an enhanced ALA-PDT protocol for nodular BCC using CP94, with no adverse reactions to this modification. This is the first time this formulation has been used in patients. This formulation is now the focus of further study.
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Donnelly RF, Curnow A, Demir YK, Singh RRT, McCarron PA, Woolfson AD (2008). Co-delivery of 5-aminolevulinic acid and the novel hydroxypyridinone iron chelator CP-94 from bioadhesive patches for enhanced topical photodynamic therapy.
JOURNAL OF PHARMACY AND PHARMACOLOGY,
60, A21-A22.
Author URL.
Pye A, Campbell S, Curnow A (2008). Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma.
J Cancer Res Clin Oncol,
134(8), 841-849.
Abstract:
Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma.
PURPOSE: Methyl-aminolevulinate (MAL) photodynamic therapy (PDT) is a cancer therapy that combines the selective accumulation of a photosensitizer in tumor tissue with visible light (and tissue oxygen) to produce reactive oxygen species. This results in cellular damage and ablation of tumor tissue. Combining iron chelators with MAL has the potential to increase the accumulation of the photosensitizer protoporphyrin IX (PpIX) by reducing its bioconversion to heme. This paper investigates this method of enhancement both in vitro and for the first time clinically for the treatment of nodular basal cell carcinoma (BCC). METHODS: Enhancement of MAL-induced PpIX accumulation by the iron chelator CP94 was quantified fluorometrically in human cultured cells (including three dermatological cell types). An open, dose-escalating, pilot study was then conducted in patients with nodular BCC, to determine the safety of this pharmacological modification. RESULTS: Large enhancements in PpIX accumulation were observed in the cultured cells when co-incubated with the iron chelator CP94. Clinically the addition of CP94 was found to be feasible and safe. In addition greater reductions in tumor depth were observed in the CP94 co-incubated tumors. CONCLUSION: Iron chelation by CP94 is an effective enhancer of MAL-induced PpIX accumulation in vitro. This method of enhancement was safely applied to a clinical PDT protocol with no unexpected adverse effects reported. Although the clinical investigation was only intended to be a small pilot to assess safety, enhancements in tumor clearance were observed both clinically and histologically when CP94 was included in the photosensitizing cream.
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Campbell SM, Curnow A (2008). Extensive vulval intraepithelial neoplasia treated with a new regime of systemic photodynamic therapy using meta-tetrahydroxychlorin (Foscan).
J Eur Acad Dermatol Venereol,
22(4), 502-503.
Author URL.
Tyrrell J, Shore A, Curnow A (2008). Monitoring clinical dermatological photodynamic therapy: validation of a noninvasive fluorescence imaging system.
Author URL.
2007
Curnow A, Peng Q (2007). 11th World Congress of the International Photodynamic Association (IPA) – meeting report.
Campbell SM, Pye A, Horton S, Matthew J, Helliwell P, Curnow A (2007). A clinical investigation to determine the effect of pressure injection on the penetration of topical methyl aminolevulinate into nodular basal cell carcinoma of the skin.
J Environ Pathol Toxicol Oncol,
26(4), 295-303.
Abstract:
A clinical investigation to determine the effect of pressure injection on the penetration of topical methyl aminolevulinate into nodular basal cell carcinoma of the skin.
This investigation considered a novel method of enhancing penetration of the topical photosensitizing agent methyl aminolevulinate (MAL) into nodular basal cell carcinomas (BCCs) using an oxygen pressure injection device. Oxygen pressure injection (OPI) is a method to drive compounds into skin using pressured oxygen. The study was an observer-blinded pilot of a single application of MAL to nBCCs, with or without the use of OPI. The BCCs were then excised at different time intervals (0-180 min) and the depth of penetration of the MAL examined using microscopic fluorescence photometry to detect the production of the naturally fluorescent active photosensitiser protoporphyrin IX (PpIX). A highly selective and homogeneous distribution of MAL-induced porphyrin fluorescence was seen in all nBCC tumors studied, and showed a high lesion-to-normal-tissue ratio with very little fluorescence in the surrounding normal tissue. Although it was difficult to compare quantitatively, as individual tumors in each of the different study groups varied, a definite trend of increase in relative tumor concentration of MAL-induced PpIX was observed over time, and this was enhanced when OPI was employed.
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Campbell S, Horton S, Curnow A (2007). A pilot study to determine the effect of pressure injection on the penetration of topical methyl aminolaevulinic acid (MAL) into nodular basal cell carcinoma (nBCC) of the skin.
Author URL.
Curnow A, Pye A (2007). Biochemical manipulation via iron chelation to enhance porphyrin production from porphyrin precursors.
Abstract:
Biochemical manipulation via iron chelation to enhance porphyrin production from porphyrin precursors.
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Pye A, Curnow A (2007). DNA damage in photodynamic therapy through the production of reactive oxygen species parallels that of ionizing radiation and UVA.
Author URL.
ACurnow, Pye A (2007). Direct comparison of delta-aminolevulinic acid and methyl-aminolevulinate-derived protoporphyrin IX accumulations potentiated by desferrioxamine or the novel hydroxypyridinone iron chelator CP94 in cultured human cells. Photochemistry and Photobiology, 83(3), 766-773.
Dogra Y, Curnow A, Winyard P (2007). Mechanisms of cell death induced by dermatological protoporphyrin IX-induced photodynamic therapy.
Author URL.
2006
Pye A, Hallaq H, Horton S, Curnow A (2006). An in vitro investigation of 5-aminolaevulinic acid and methyl aminotaevulinate photodynamic therapy enhancement by iron removal using CP94.
Author URL.
Pye AJ, Wakeman TD, Horton SJ, Campbell SM, Salter L, Curnow A (2006). An in vitro investigation of the genotoxic role of iron during aminolaevulinic acid photodynamic therapy.
Author URL.
Curnow A, MacRobert AJ, Bown SG (2006). Comparing and combining light dose fractionation and iron chelation to enhance experimental photodynamic therapy with aminolevulinic acid.
Lasers Surg Med,
38(4), 325-331.
Abstract:
Comparing and combining light dose fractionation and iron chelation to enhance experimental photodynamic therapy with aminolevulinic acid.
BACKGROUND AND OBJECTIVES: Enhancement of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) has been demonstrated experimentally using light dose fractionation or CP94 iron chelation. This study extends this research. STUDY DESIGN/MATERIALS AND METHODS: in normal rat colon, CP94 administration and light dose fractionation were independently and concurrently employed to enhance ALA-PDT. In colonic rat tumors, the most successful enhancement regimes were employed separately. RESULTS: Independent use of light dose fractionation and iron chelation produced similar results in normal colon (2.4- and 2.9-fold more necrosis than controls, respectively). Using both techniques simultaneously produced fivefold enhancement. In the colonic tumors, light dose fractionation and iron chelation (using different parameters) produced two and five times the volume of necrosis, respectively. CONCLUSIONS: Both techniques significantly enhanced ALA-PDT in the normal and neoplastic tissues investigated and produced similar levels of enhancement when comparable parameters were employed. Concurrent use of light dose fractionation and iron chelation in normal colon produced considerably more enhancement than either technique could achieve independently.
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Adie K, Moody A, Pye A, Curnow A (2006). Does chronic therapeutic paracetamol use predispose to oxidative stress?.
Bradfield W, Pye A, Clifford T, Salter L, Gould D, Campbell S, Curnow A (2006). Hg(II) exposure exacerbates UV-induced DNA damage in MRC5 fibroblasts: a comet assay study.
J Environ Sci Health a Tox Hazard Subst Environ Eng,
41(2), 143-148.
Abstract:
Hg(II) exposure exacerbates UV-induced DNA damage in MRC5 fibroblasts: a comet assay study.
When exposed to UVR, MRC5 fibroblasts incubated with mercuric chloride (0-15 microM) for 1 hour show increased DNA damage (as measured by the comet assay) compared to control cells (UVR irradiated but no mercuric chloride). This demonstrates that mercuric chloride and UVR in combination increase DNA damage in a synergistic manner. This may have implications to those exposed to mercury as it suggests that exposure to mercury in the environment may increase sensitivity to sunlight-induced carcinogenesis.
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Curnow A (2006). Potential Future Indications. In Pottier R, Krammer B, Stepp H, Baumgartner R (Eds.) Photodynamic therapy with ALA: a clinical handbook, Cambridge: Royal Society of Chemistry, 249-259.
Morley N, Rapp A, Dittmar H, Salter L, Gould D, Greulich KO, Curnow A (2006). UVA-induced apoptosis studied by the new apo/necro-Comet-assay which distinguishes viable, apoptotic and necrotic cells.
Mutagenesis,
21(2), 105-114.
Abstract:
UVA-induced apoptosis studied by the new apo/necro-Comet-assay which distinguishes viable, apoptotic and necrotic cells.
An adaptation of the Comet-assay was developed which enables the discrimination of viable, apoptotic and necrotic single cells by use of the common Annexin-V staining and a dye exclusion test on the cells already embedded in agarose gel on glass slides. Membrane integrity (Ethidium-Homodimer exclusion), cellular esterase activity (Calcein blue-AM) as well as translocation of phosphadidyl-serine (Annexin-V) were analysed using these stains. The advantage of the 'apo/necro-Comet-assay' is that the viability status of individual cells can be determined and correlated with the DNA fragmentation pattern (comet) formed by the same cells. Hence, DNA damage can be assessed and correlated with viable cells or cells undergoing early, mid- or late stage apoptosis or necrosis as identified by the staining pattern. The staining was verified using heat and etoposide-induced apoptosis. This technique, among others, was used to study whether apoptotic fragmentation interferes with repair kinetics measured with the comet assay following UVA exposure (doses up to 1,280 kJ/m(2)) in the cultured human keratinocytes (HaCaT). Therefore, a time course of apoptotic events (phosphatidyl translocation and TUNEL fragmentation) was established and correlated to the DNA fragmentation in the comet-assay. Apoptotic cells were detected more than 8 h later. The combined three-colour staining method with the comet assay showed that there was no significant interference of DNA repair by apoptotic fragmentation processes since DNA repair was almost completed before the onset of apoptotic fragmentation. The apo/necro-Comet-assay reduces the general problem of false-positive results in genotoxicity tests using the Comet-assay.
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Author URL.
2005
Pye AJ, Campbell SM, Horton SJ, Salter L, Curnow A (2005). An in vitro investigation of the enhancement of 5-aminolaevulinic acid-induced photodynamic therapy for the treatment of nodular basal cell carcinoma using the hydroxypyridinone iron chelator CP94.
Author URL.
Curnow A, Campbell S, Leman J, Morton C, Salter L (2005). Enhancement of dermatological ALA-PDT with an iron chelating agent (CP94).
Campbell S, Gould D, Salter L, Curnow A (2005). Penile intraepidermal neoplasia treated with MAL-PDT.
Author URL.
Morley N, Clifford T, Salter L, Campbell S, Gould D, Curnow A (2005). The green tea polyphenol (-)-epigallocatechin gallate and green tea can protect human cellular DNA from ultraviolet and visible radiation-induced damage.
Photodermatol Photoimmunol Photomed,
21(1), 15-22.
Abstract:
The green tea polyphenol (-)-epigallocatechin gallate and green tea can protect human cellular DNA from ultraviolet and visible radiation-induced damage.
BACKGROUND: Antioxidant compounds in green tea may be able to protect against skin carcinogenesis and it is of interest to investigate the mechanisms involved. A study was therefore conducted to determine whether the isolated green tea polyphenol (-)-epigallocatechin gallate (EGCG) could prevent ultraviolet radiation (UVR)-induced DNA damage in cultured human cells. This work was then extended to investigate whether drinking green tea could afford any UVR protection to human peripheral blood cells collected after tea ingestion. METHODS: the alkaline comet assay was used to compare the DNA damage induced by UVR in cultured human cells with and without the presence of EGCG. The same assay technique was then employed to assess UVR-induced DNA damage in peripheral leucocytes isolated from 10 adult human volunteers before and after drinking 540 ml of green tea. RESULTS: Initial trials found that EGCG afforded concentration-dependent photoprotection to cultured human cells with a maximal activity at a culture concentration of 250 microM. The cells types tested (lung fibroblasts, skin fibroblasts and epidermal keratinocytes) demonstrated varying susceptibility to the UVR insult provided. The in vivo trials of green tea also demonstrated a photoprotective effect, with samples of peripheral blood cells taken after green tea consumption showing lower levels of DNA damage than those taken prior to ingestion when exposed to 12 min ultraviolet a (UVA) radiation. CONCLUSION: the studies showed that green tea and/or some constituents can offer some protection against UV-induced DNA damage in human cell cultures and also in human peripheral blood samples taken post-tea ingestion.
Abstract.
Author URL.
2004
Campbell SM, Gould DJ, Salter L, Clifford T, Curnow A (2004). Photodynamic therapy using meta-tetrahydroxyphenylchlorin (Foscan) for the treatment of vulval intraepithelial neoplasia.
Br J Dermatol,
151(5), 1076-1080.
Abstract:
Photodynamic therapy using meta-tetrahydroxyphenylchlorin (Foscan) for the treatment of vulval intraepithelial neoplasia.
BACKGROUND: Photodynamic therapy (PDT) has unique properties which make it suitable for the local treatment of superficial epithelial disorders; it has been suggested as a useful treatment for carcinoma in situ of the vulva. OBJECTIVES: to evaluate the effect of the systemic photosensitizing agent meta-tetrahydroxyphenylchlorin (mTHPC or temoporfin; Foscan, Biolitec, Edinburgh, U.K.) in vulval intraepithelial neoplasia type III (VIN III). METHODS: PDT using mTHPC was performed in six patients with VIN III. A dose of 0.1 mg kg(-1) body weight mTHPC was injected intravenously and the area of VIN irradiated 96 h later with 652-nm light from a diode laser. Patients were reviewed 1 week, 6 months and 2 years following treatment. RESULTS: Patients experienced only minimal pain from the initial treatment but two patients subsequently developed severe pain at the treated site for up to 2 weeks following PDT. All patients developed oedema and slough formation at the treated site and one patient developed cellulitis. At 6 months two patients had developed small recurrences of VIN at the original site and one patient had an area of VIN at a new site. These were treated either with further PDT or with a small excision. At 2 years there was no recurrence of VIN at the original site in all patients reviewed. CONCLUSIONS: This small case series demonstrates that mTHPC-PDT is a useful initial treatment for VIN III. It is relatively selective, shows good cosmesis and conserves form and function. This is a major advantage over surgery. Repeat treatments are also possible, which is important in a condition such as VIN, which tends to be multifocal. Systemic mTHPC-PDT appears to have an advantage over topical 5-aminolaevulinic acid-PDT as the photosensitizer is distributed widely in areas of disease and consequently identifies foci which may not be apparent clinically but become evident when illuminated.
Abstract.
Author URL.
Morley N, Clifford T, Salter L, Campbell S, Gould D, Pye A, Curnow A (2004). The green tea polyphenol (-)-epigallocatechin gallate and green tea can protect human cellular DNA from ultraviolet and visible radiation-induced damage.
Author URL.
Salter L, Clifford T, Morley N, Gould D, Campbell S, Curnow A (2004). The use of comet assay data with a simple reaction mechanism to evaluate the relative effectiveness of free radical scavenging by quercetin, epigallocatechin gallate and N-acetylcysteine in UV-irradiated MRC5 lung fibroblasts.
J Photochem Photobiol B,
75(1-2), 57-61.
Abstract:
The use of comet assay data with a simple reaction mechanism to evaluate the relative effectiveness of free radical scavenging by quercetin, epigallocatechin gallate and N-acetylcysteine in UV-irradiated MRC5 lung fibroblasts.
Comet assay data (tail DNA %) have been gathered for the concentration dependent role of three antioxidants (AOs); quercetin (Q), epigallocatechin gallate (EGCG) and N-acetylcysteine (NAC) in reducing UV-induced damage to DNA in normal fetal lung fibroblasts (MRC5). All three compounds demonstrate a concentration dependent reduction maximum with a pro-oxidant effect at higher (though not cytotoxic) concentrations. Manipulation of a simple 4-step reaction mechanism for free radical (FR) scavenging by AOs produced rate constant ratios which allowed the relative effectiveness (Q > EGCG > NAC) of the AOs to be evaluated.
Abstract.
Author URL.
Morton CA, Campbell S, Gould D, Curnow A (2004). Topical photodynamic therapy with the iron chelator, CP94, for nodular basal cell carcinoma.
Author URL.
2003
Campbell S, Leman J, Curnow A, Morton C, Salter L, Gould D (2003). Enhancing dermatological 5-aminolaevulinic acid-photodynamic therapy with a novel iron chelator.
Author URL.
Morley N, Curnow A, Salter L, Campbell S, Gould D (2003). N-acetyl-L-cysteine prevents DNA damage induced by UVA, UVB and visible radiation in human fibroblasts.
J Photochem Photobiol B,
72(1-3), 55-60.
Abstract:
N-acetyl-L-cysteine prevents DNA damage induced by UVA, UVB and visible radiation in human fibroblasts.
The thiol N-acetyl-L-cysteine (NAC) is a source of cysteine for the synthesis of the endogenous antioxidant glutathione (GSH) which is depleted by ultraviolet radiation. It is also associated with the scavenging of reactive oxygen species (ROS). In this study the effects of NAC were examined in cultured human fibroblasts during prolonged exposure to ultraviolet B (UVB), ultraviolet a (UVA) and visible irradiation (280-700 nm), delivered by a 150 W xenon-arc lamp. The alkaline comet assay was used to assess the DNA damage in individual cells. It was found that incubating skin and lung fibroblasts at 37 degrees C for 1 h with an optimal 6 mM NAC supplement prior to light exposure, significantly reduced the level of DNA damage in both cell types, however, the skin fibroblasts were less sensitive to xenon-arc lamp irradiation than lung fibroblasts. NAC incubation resulted in an initial delay in DNA damage when the cells were irradiated. There was also a significant reduction in the overall levels of DNA damage observed with continued irradiation. NAC significantly reduced the DNA damage produced in lung fibroblasts depleted of normal GSH protection by the glutamylcysteinyl synthetase inhibitor, L-buthionine-[S,R]-sulfoximine. Although the specific mechanism of NAC protection has not yet been elucidated, these results support the hypothesis that NAC may protect the cells directly, by scavenging ROS induced by UVA and visible radiation, and indirectly by donating cysteine for GSH synthesis.
Abstract.
Author URL.
Gould D, Curnow A, Morley N, Salter L (2003). Synergy between pollutants and ultraviolet radiation: a comet assay investigation.
Author URL.
Morley RN, Dittmar H, Curnow A, Salter L, Gould D, Greulich KO (2003). Two waves of apoptosis occur after UV-A exposure as detected with repeated scanning comet-assay.
Author URL.
2002
Stentiford FWM, Morley N, Curnow A (2002). Automatic identification of regions of interest with application to the quantification of DNA damage in cells.
Author URL.
Kömerik N, Curnow A, MacRobert AJ, Hopper C, Speight PM, Wilson M (2002). Fluorescence biodistribution and photosensitising activity of toluidine blue o on rat buccal mucosa.
Lasers Med Sci,
17(2), 86-92.
Abstract:
Fluorescence biodistribution and photosensitising activity of toluidine blue o on rat buccal mucosa.
The antimicrobial activity of toluidine blue O (TBO) in the presence of red light has been demonstrated for a wide range of microorganisms. The response of tissues to TBO-induced photosensitisation is an important factor in assessing the clinical usefulness of this technique for the treatment of infectious diseases. The aims of this study were to determine the effect of TBO-mediated photosensitisation on rat buccal mucosa and the biodistribution of the photosensitiser in this tissue. An aqueous solution of TBO was applied to one side of the buccal mucosa of the animals. A 6 mm diameter area was then exposed to light (633 nm) from a copper vapour pumped-dye laser. The opposite, untreated, side of the buccal mucosa served as a control. TBO concentrations of 25, 50 and 200 microg/ml, laser light doses of 110, 170 and 340 J/cm(2) were assessed. Control groups of animals were subjected to 340 J/cm(2) laser light alone or to 200 microg/ml TBO alone. Serial sacrifices were performed after 72 h to obtain mucosal tissue samples for histological examination. For the determination of TBO biodistribution, additional groups received the same TBO doses and were sacrificed after 1 min or 10 min. Specimens were removed and frozen immediately for digital fluorescence imaging. No necrotic or inflammatory changes were found in the buccal mucosa of the animals with any of the treatments (using up to 200 microg/ml TBO and 340 J/cm(2) laser light). A high TBO fluorescence in the epithelium, particularly in the keratinised layer, with almost no fluorescence in the underlying connective tissue was demonstrated by the digital imaging. The results of this study suggest that TBO-mediated PDT (within the concentrations and light doses tested) could be a safe antimicrobial approach for the oral infections without damaging the adjacent normal tissue.
Abstract.
Author URL.
Tsutsui H, MacRobert AJ, Curnow A, Rogowska A, Buonaccorsi G, Kato H, Bown SG (2002). Optimisation of illumination for photodynamic therapy with mTHPC on normal colon and a transplantable tumour in rats.
Lasers Med Sci,
17(2), 101-109.
Abstract:
Optimisation of illumination for photodynamic therapy with mTHPC on normal colon and a transplantable tumour in rats.
Recent reports suggest that the effect of photodynamic therapy (PDT) can be enhanced by fractionating the light dose or reducing the light fluence rate. We assessed these options on two tissues in rats (normal colon and a transplanted fibrosarcoma) using the photosensitiser meta-tetrahydroxyphenylchlorin (mTHPC). Animals were sensitised with 0.3 mg/kg mTHPC, 3 days prior to illumination with red light (652 nm) using a single fibre touching the target tissue and killed 1-3 days later for quantitative measurement of the extent of PDT necrosis. Results were similar for both tissues, although the differences between illumination regimens were less marked in tumour tissue. Using continuous illumination and a fixed low energy in colon, the extent of necrosis was up to almost three times larger with 5 mW than with 100 mW, although the maximum attainable necrosis was independent of power. The long treatment time using 5 mW could be halved without loss of effect by increasing the power during treatment. Dividing the light into two equal fractions at 100 mW increased the lesion size by up to 20% in colon (independent of the timing of the dark interval), but by only 10% in tumour and had no effect at 20 mW. Previous studies using 5-aminolaevulinic acid (ALA) showed a much larger effect of fractionation that was critically dependent on the timing of the dark interval. We postulate that enhancement of PDT by fractionation is due to improved oxygen supply to the treated area which may be due to reversal of temporary vascular occlusion (more likely with ALA) or less rapid photochemical consumption of oxygen (more likely with mTHPC). At lower fluence rates, the oxygen consumption rate is not fast enough to be improved by fractionation. We conclude that fractionated or low power light delivery can enhance PDT with mTHPC. Although the effects are not large, this may be of value for interstitial treatment of solid tumours when multiple sites are treated simultaneously.
Abstract.
Author URL.
Curnow A, Salter L, Morley N, Campbell S, Gould D (2002). Paracetamol can exacerbate irradiation-induced DNA damage.
Br J Clin Pharmacol,
53(3), 338-340.
Author URL.
Curnow A, Bown SG (2002). The role of reperfusion injury in photodynamic therapy with 5-aminolaevulinic acid--a study on normal rat colon.
Br J Cancer,
86(6), 989-992.
Abstract:
The role of reperfusion injury in photodynamic therapy with 5-aminolaevulinic acid--a study on normal rat colon.
Reperfusion injury can occur when blood flow is restored after a transient period of ischaemia. The resulting cascade of reactive oxygen species damages tissue. This mechanism may contribute to the tissue damage produced by 5-aminolaevulinic acid-induced photodynamic therapy, if this treatment temporarily depletes oxygen in an area that is subsequently reoxygenated. This was investigated in the normal colon of female Wistar rats. All animals received 200 mg kg(-1) 5-aminolaevulinic acid intravenously 2 h prior to 25 J (100 mW) of 628 nm light, which was delivered continuously or fractionated (5 J/150 second dark interval/20 J). Animals were recovered following surgery, killed 3 days later and the photodynamic therapy lesion measured macroscopically. The effects of reperfusion injury were removed from the experiments either through the administration of free radical scavengers (superoxide dismutase (10 mg kg(-1)) and catalase (7.5 mg kg(-1)) in combination) or allopurinol (an inhibitor of xanthine oxidase (50 mg kg(-1))). Prior administration of the free radical scavengers and allopurinol abolished the macroscopic damage produced by 5-aminolaevulinic acid photodynamic therapy in this model, regardless of the light regime employed. As the specific inhibitor of xanthine oxidase (allopurinol) protected against photodynamic therapy damage, it is concluded that reperfusion injury is involved in the mechanism of photodynamic therapy in the rat colon.
Abstract.
Author URL.
ACurnow, Bown S (2002). The role of reperfusion injury in photodynamic therapy with aminolaevulinic acid - a study on normal rat colon. British Journal of Cancer, 86(6), 989-992.
2001
Curnow A, Salter L, Morley N, Gould D (2001). A preliminary investigation of the effects of arsenate on irradiation-induced DNA damage in cultured human lung fibroblasts.
J Toxicol Environ Health A,
63(8), 605-616.
Abstract:
A preliminary investigation of the effects of arsenate on irradiation-induced DNA damage in cultured human lung fibroblasts.
Single-cell gel electrophoresis (the comet assay) was used to assess single-strand breaks (SSBs) produced in cultured lung human fibroblasts by xenon lamp irradiation alone, various concentrations of arsenate [As(V)], alone or various combinations of the two. It was found that significantly higher levels of SSBs were observed in the irradiated cells than the nonirradiated cells and that elevating levels of arsenate enhanced the level of damage detected in both irradiated and nonirradiated cells in a concentration-dependent manner; that is, incubating cells with arsenate alone produced marked DNA damage without an irradiation insult being necessary. The results of this study indicate that arsenate is acting as a cogenotoxin with irradiation in this cell line. This additive effect may also be cocarcinogenic, and as a result it is possible that less solar irradiation may be required to induce skin cancer in arsenic-exposed populations.
Abstract.
Author URL.
Curnow A, Parsons B, Salter L, Morley N, Gould D (2001). An investigation of the genotoxic effects of airborne particulate matter using single-cell gel electrophoresis.
Abstract:
An investigation of the genotoxic effects of airborne particulate matter using single-cell gel electrophoresis
Abstract.
Curnow A, Parsons B, Salter L, Morley N, Gould D (2001). An investigation of the genotoxic effects of airborne particulate matter using single-cell gel electrophoresis.
Indoor and Built Environment,
10(3-4), 258-260.
Abstract:
An investigation of the genotoxic effects of airborne particulate matter using single-cell gel electrophoresis
Samples of the PM10 fraction of airborne particulate matter were collected from a roadside location in Cornwall using a Partisol 2000 gravimetric air sampler. Cultured human lung fibroblasts were exposed to a sonicated extract of this matter for various periods of time (0-120 h) and the presence of DNA damage was then assessed using single-cell gel electrophoresis. Four times the level of DNA damage was detected in the PM10-exposed cells than that observed in similarly treated but non-PM10-exposed control cells. This indicates that the airborne PM10from this site has significant genotoxic effects in this experimental system and that single-cell gel electrophoresis is a useful technique for the assessment of this form of particulate matter-induced biological damage. Copyright © 2002 S. Karger AG, Basel.
Abstract.
2000
Curnow A, Gould D, Salter L (2000). A new method for the cultivation of human naevus melanocytes.
Connell RJ, Curnow A, Cutner A, Brown S (2000). Endometrial ablation in the rabbit uterus by photodynamic therapy (PDT) using 5-aminolaevulinic acid with the iron chelator CP94.
BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY,
107(6), 828-828.
Author URL.
Curnow A, Haller JC, Bown SG (2000). Oxygen monitoring during 5-aminolaevulinic acid induced photodynamic therapy in normal rat colon. Comparison of continuous and fractionated light regimes.
J Photochem Photobiol B,
58(2-3), 149-155.
Abstract:
Oxygen monitoring during 5-aminolaevulinic acid induced photodynamic therapy in normal rat colon. Comparison of continuous and fractionated light regimes.
Currently, the clinical use of 5-aminolaevulinic acid (ALA) induced protoporphyrin IX (PPIX) for photodynamic therapy (PDT) is limited by the maximum tolerated oral ALA dose (60 mg/kg). Attempts have been made to enhance this treatment modality without increasing the administered dose of ALA. One way to do this is through light dose fractionation, where the irradiation is interrupted at a particular point for a short period of time. This can produce up to three times more necrosis than with the same light dose delivered without a break. An oxygen microelectrode was employed to study the effect of continuous and fractionated light regimes on the level of oxygen in the colon of normal Wistar rats during ALA PDT. A rapid decline in pO2 occurred close to the irradiation fibre as soon as the light dose commenced. With the fractionated regime, a partial recovery in pO2 was observed during the dark interval which was reversed soon after the second light fraction commenced. We have shown that the level of tissue oxygen at the treatment site is affected differently when the light dose is fractionated, than when continuous illumination is employed. This factor may at least partially explain the difference in outcome of these two treatment regimes. Further, oxygen measurements might prove to be a useful way of monitoring PDT treatments if they can predict whether tissue is likely to be viable following treatment.
Abstract.
Author URL.
1999
Curnow A, McIlroy BW, Postle-Hacon MJ, MacRobert AJ, Bown SG (1999). Light dose fractionation to enhance photodynamic therapy using 5-aminolevulinic acid in the normal rat colon.
Photochem Photobiol,
69(1), 71-76.
Abstract:
Light dose fractionation to enhance photodynamic therapy using 5-aminolevulinic acid in the normal rat colon.
5-Aminolevulinic acid (ALA) is an attractive photosensitizing agent for photodynamic therapy (PDT) as its photoactive derivative, protoporphyrin IX, is metabolized within 1-2 days, eliminating prolonged skin photosensitivity. However, at the maximum dose patients can tolerate by mouth, 60 mg/kg, only superficial effects are seen. This paper extends earlier studies on enhancing the effect by light fractionation. Experiments in the normal rat colon looked at the area of necrosis around a single light delivery fiber 3 days after PDT with a range of light-dose fractionation regimes. All animals were given 200 mg/kg ALA intravenously 2 h prior to light delivery (100 mW at 635 nm) and each interruption in illumination was for 150 s. The area of PDT necrosis (total dose 25 J) could be increased by a factor of 3 with a single interval after 5 J, compared with continuous illumination. Alternatively, with this single break, the total light dose could be reduced by 60% to achieve the same area of necrosis as with continuous illumination. This simple modification to PDT with ALA could markedly reduce current treatment times as well as increasing clinical efficacy.
Abstract.
Author URL.
1998
Curnow A, McIlroy B, Postle-Hacon M, Porter J, MacRobert A, Bown S (1998). Enhancement of 5-aminolaevulinic acid induced photodynamic therapy using iron chelating agents. British Journal of Cancer, 78, 1278-1282.
Curnow A, Postle-Hacon MJ, MacRobert AJ, Brown SG (1998). Enhancement of 5-aminolaevulinic acid induced photodynamic therapy using light dose fractionation and iron chelating agents.
Author URL.
Curnow A, McIlroy BW, Postle-Hacon MJ, Porter JB, MacRobert AJ, Bown SG (1998). Enhancement of 5-aminolaevulinic acid-induced photodynamic therapy in normal rat colon using hydroxypyridinone iron-chelating agents.
Br J Cancer,
78(10), 1278-1282.
Abstract:
Enhancement of 5-aminolaevulinic acid-induced photodynamic therapy in normal rat colon using hydroxypyridinone iron-chelating agents.
Currently, the clinical use of 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PPIX) for photodynamic therapy (PDT) is limited by the maximum tolerated oral ALA dose (60 mg kg(-1)). This study investigates whether hydroxypyridinone iron-chelating agents can be used to enhance the tissue levels of PPIX, without increasing the administered dose of ALA. Quantitative charge-coupled device (CCD) fluorescence microscopy was employed to study PPIX fluorescence pharmacokinetics in the colon of normal Wistar rats. The iron chelator, CP94, when administered with ALA was found to produce double the PPIX fluorescence in the colonic mucosa, compared with the same dose of ALA given alone and to be more effective than the other iron chelator studied, CP20. Microspectrofluorimetric studies demonstrated that PPIX was the predominant porphyrin species present. PDT studies conducted on the colonic mucosa showed that the simultaneous administration of 100 mg kg(-1) CP94 i.v. and 50 mg kg(-1) ALA i.v. produced an area of necrosis three times larger than similar parameters without the iron-chelating agent with the same light dose. It is possible, therefore, to increase the amount of necrosis produced by ALA-induced PDT substantially, without increasing the administered dose of ALA, through the simultaneous administration of the iron-chelating agent, CP94.
Abstract.
Author URL.
McIlroy BW, Curnow A, Buonaccorsi G, Scott MA, Bown SG, MacRobert AJ (1998). Spatial measurement of oxygen levels during photodynamic therapy using time-resolved optical spectroscopy.
J Photochem Photobiol B,
43(1), 47-55.
Abstract:
Spatial measurement of oxygen levels during photodynamic therapy using time-resolved optical spectroscopy.
Tissue oxygenation is one of the key dosimetric factors involved in the application of photodynamic therapy (PDT). However, quantitative studies of oxygenation levels at and surrounding the treatment site have been lacking both before, during and after treatment. With the recent development of sensitive, non-invasive, optical spectroscopic techniques based on oxygen-dependent phosphorescence quenching of probe compounds, oxygenation levels can now be measured quantitatively at selected sites with spatial resolution on the millimeter scale. We present results using the phosphorescent compound, palladium meso-tetra(carboxyphenyl)porphine, for measurement of in vivo microvascular oxygen tensions in rat liver during PDT. Time-resolved phosphorescence detection was carried out using fibre-optic sensoring, and oxygen tensions were determined from the phosphorescence lifetimes using Stern-Volmer analysis. During PDT treatment using 5-aminolaevulinic (ALA) acid-induced protoporphyrin IX (PPIX) with a 50 mg/kg ALA dose, oxygen levels near the irradiation fibre placed on the surface of the liver showed a significant decrease by a factor of ten from 20 to 2 torr after an energy dose of 60 J using 100 mW at 635 nm. Areas farther from the treatment site which were exposed to lower light doses exhibited lower reductions in oxygen levels. This spectroscopic technique is a highly sensitive means of investigating tissue oxygenation during and after treatment, and should help not only to advance the understanding of hypoxia and microvascular damage in the PDT mechanism but also contribute to improving the dosimetry of PDT.
Abstract.
Author URL.
Komerik N, Speight P, Curnow A, Postle-Hacon M, Wilson M, Hopper C (1998). The effect of photodynamic therapy on rat buccal mucosa.
JOURNAL OF DENTAL RESEARCH,
77, 754-754.
Author URL.
1994
Twelves CJ, Dobbs NA, Curnow A, Coleman RE, Stewart AL, Tyrrell CJ, Canney P, Rubens RD (1994). A phase II, multicentre, UK study of vinorelbine in advanced breast cancer.
Br J Cancer,
70(5), 990-993.
Abstract:
A phase II, multicentre, UK study of vinorelbine in advanced breast cancer.
Thirty-four evaluable patients were treated with vinorelbine, a novel, semisynthetic vinca alkaloid, as first-line chemotherapy for advanced breast cancer. They received vinorelbine 25 mg m-2 i.v. given weekly for a maximum of 16 cycles. Two patients achieved a complete remission and 15 a partial remission, giving a response rate of 17/34 (50%; 95% CI of 34-66%); median response duration was 5.8 months. The median progression-free interval was 4.4 months and median survival 9.9 months. Treatment was generally well tolerated. Fatigue was the most common side-effect. The main reason for dose adjustments was myelosuppression; 68% of patients had WHO grade 3 or 4 neutropenia and there was one death attributed to neutropenic sepsis. Nausea/vomiting and neuropathy were mild and alopecia was uncommon. This study confirms vinorelbine as a highly active, well-tolerated agent in advanced breast cancer worthy of evaluation in combination chemotherapy regimens.
Abstract.
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