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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Rice, Lesley
Languages: English
Types: Doctoral thesis
Subjects: B110
Photodynamic therapy (PDT) is a novel treatment for malignant disease. The first step is intravenous injection of a light-absorbing, cytotoxic drug (the photosensitizer) that is then allowed time to accumulate in malignant tissue. The second step involves local activation of the photosensitizer with long (red) wavelength light, delivered usually from a laser. Subsequent to irradiation, highly reactive singlet molecular oxygen (Type II mechanism) is likely to be the most damaging cytotoxic species in vivo. The porphyrin molecule, Photofrin®, is the only photosensitizer currently registered for clinical use but is associated with several problems. Most disappointing is the fact that Photofrin® accumulates not only in malignant tissue but also in other organs, such as the liver, kidney and spleen. Its long persistence in the skin commonly causes severe photosensitization reactions in patients for up to three months post-treatment. Photofrin® also has poor light absorption properties within the therapeutic window (600 to 800 nm) for PDT. Furthermore, PDT with Photofrin® has proved of no use in the treatment of malignant melanoma due, possibly, to competition between the photosensitizer and melanin for light absorption.\ud \ud Second-generation photosensitizers have tended to be porphyrin-based molecules, many of which have reached various stages of clinical trial. Of non porphyrin-based compounds, the cationic dye, methylene blue (MB), used traditionally as a nuclear stain in histology, has proved also to be an efficient photosensitizer, with maximum light absorption properties within the therapeutic window for PDT. Its use as a selective stain for tumour tissue in the bladder led first to its investigation in humans for the PDT of bladder cancer and inoperable tumours of the oesophagus. Radiolabelled MB has also recently been used as a tracer for metastatic melanoma in humans. The disadvantages of MB are an inherent (dark) toxicity and its rapid reduction in vivo to the inactive form, leuco-methylene blue (LMIB).\ud \ud This study found the cytotoxicity of MB to be enhanced by illumination and that successive methylation of the molecule corresponds to both increased light and dark toxicities in the EMT-6 (murine mammary), the SK-23 (murine melanoma) and SKMEL-28 (human melanoma) cell lines. The increased toxicities may be due to increased resistance to reduction (MBcNMB.cMMB
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