Aminolevulinic acid photodynamic therapy (ALA-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. The use of iron chelators in combination with ALA has the potential to increase the accumulation of the photosensitizer protoporphyrin IX (PpIX) by reducing its bioconversion to heme. This study compares directly for the first time the effects of the novel hydroxypyridinone iron chelating agent CP94 and the more clinically established iron chelator desferrioxamine (DFO) on the enhancement of ALA and methyl-aminolevulinate (MAL)-induced PpIX accumulations in cultured human cells. Cultured human cells were incubated with a combination of ALA, MAL, CP94 and DFO concentrations; the resulting PpIX accumulations being quantified fluorometrically. The use of iron chelators in combination with ALA or MAL was shown to significantly increase the amount of PpIX accumulating in the fetal lung fibroblasts and epidermal carcinoma cells; while minimal enhancement was observed in the normal skin cells investigated (fibroblasts and keratinocytes). Where enhancement was observed CP94 was shown to be significantly superior to DFO in the enhancement of PpIX accumulation.

Background: Photodynamic therapy (PDT) involves the activation of a photosensitiser 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's 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.The aim of this study was to assess the safety and efficacy of adding a novel iron chelating agent, CP94 to topical ALA, to increase the accumulation of the photosensitiser in the tumour.Observations: 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. Conclusion: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.

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 coincubated 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 coincubated tumors. Conclusion:Iron chelation by CP94 is an effective enhancer of MAL-induced PpIX accumulation in vitro.

Background: Protoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being

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.

Topical protoporphyrin IX (PPIX) induced photodynamic therapy (PDT) of basal cell carcinoma (BCC) produces good clinical outcomes with excellent cosmesis as long as the disease remains superficial. Efficacy for nodular BCC, however, appears inferior to standard treatment unless repeat treatments are performed. Enhancement is therefore required and may be possible by employing iron chelating agents to temporarily increase PPIX accumulation above the levels normally obtained using aminolaevulinic acid (ALA) or the methyl ester of ALA (MAL) alone. In vitro studies investigated the efficacies of the novel iron chelator, CP94 (1,2-diethyl-3-hydroxypyridin-4-one hydrochloride), and the established iron chelator, desferrioxamine (DFO), at increasing PPIX fluorescence in cultured human lung fibroblasts and squamous carcinoma cells incubated with ALA/MAL. CP94 was found to produce greater PPIX fluorescence when administered with ALA/MAL than either congener could produce alone. CP94 was also found to be superior to DFO in the enhancement of PPIX fluorescence and could be employed to accumulate the same levels of PPIX within a shorter time period. Clinical utilization of CP94 to enhance ALA/MAL-PDT could potentially result in greater PPIX accumulation or alternatively could be employed to reduce the length of the required drug-light interval. Clinical investigation of this is currently underway.

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.

This work was carried out as a collaboration between all authors. Author AD led the design of the study, planned the data collection, led the workshop discussion on co-creation of research and led the writing of the manuscript. Author DM provided guidance on methods of qualitative analyses, supported coordination of the data collection and assisted in shaping the paper. Authors JH, AEK, AP led the workshop discussions on co-creation of education resources (JH) and peer support (AK and AP) and, provided subject-specific knowledge in these areas in the paper. Author NTG provided extensive support in coordinating the workshop, carried out much of the data analysis for the paper in collaboration with Author AD and produced the tables of data. All authors read and approved the final manuscript.