benzoporphyrin-d and temoporfin

Recent studies have demonstrated an effect of photodamage on the endocytic pathway involved in recycling of membrane components. Using a series of agents with known sub-cellular targets, we explored the determinants of photodynamic inhibition of endocytic processes in three cell lines: A murine leukemia, a murine hepatoma, and a non-malignant epithelial cell line of human origin.. The PI-3 kinase antagonist wortmannin blocks endosomal processing pathway dependent on this enzyme, providing an indication of the "flux" of endocytosis. Microscopic observations were used to assess the effect of photodamage on this pathway. Photosensitizing agents specific for mitochondrial, endoplasmic reticulum (ER), lysosomal, and endosomal photodamage were employed.. Sub-lethal photodamage directed against endosomes or lysosomes interrupted early steps in this endocytic process in the hepatoma cell line. A mechanism for these effects is proposed. Mitochondrial photodamage could interrupt endocytosis, but at levels that also induced apoptosis. ER photodamage did not affect endocytosis even at lethal levels. Somewhat similar results were obtained with other cell lines, but there were sufficient differences to indicate that the cell phenotype is, in part, a determinant of the endocytic response to PDT.. PDT is therefore seen to have an effect on endocytic processes. Further work will be needed to delineate the role of these endocytic effects in the array of responses to photodynamic therapy.

Topics: Androstadienes; Animals; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Endocytosis; Epithelial Cells; Humans; Indoles; Leukemia; Liver Neoplasms; Mesoporphyrins; Mice; Models, Biological; Organelles; Organometallic Compounds; Phosphodiesterase Inhibitors; Photochemotherapy; Photosensitizing Agents; Porphyrins; Wortmannin

The pharmacokinetics of the photosensitizer used play a key role in the understanding of the mechanism of photodynamic therapy-induced damage. Fluorescence microscopy was used to compare time-dependent biodistribution of tetra(m-hydroxyphenyl)chlorin (mTHPC) and benzoporphyrin derivative monoacid ring A (BPD-MA) in different hamster tissues, including an early, chemically induced, squamous cell carcinoma. Following injection of 0.5 mg/kg body weight of mTHPC and 2.0 mg/kg BPD-MA, groups of three animals were sacrificed at different time points and a series of fluorescence micrographs from different excised organs were analyzed. The highest fluorescence intensities of mTHPC were observed at 96 h for squamous epithelia and skin and at 48 h for smooth muscle. There is no real peak of BPD-MA fluorescence between 30 min and 3 h in the basal epithelial layers, fibroconnective tissue, muscles or blood vessels. At 4 h after injection, the fluorescence level of BPD-MA decreased and at 24 h it had returned to background level in all observed tissues. The significantly faster clearance of BPD-MA is the principal advantage as compared to mTHPC. However, similar localization patterns in different tissues with essentially vascular affinity represent a possible disadvantage for treating early malignancies with BPD-MA as compared to mTHPC, which is mainly localized in various epithelia. For both photosensitizers no significant selectivity between early squamous cell carcinoma and healthy mucosae is seen. Pharmacokinetic studies of different photosensitizers in an appropriate animal model are essential for selecting new-generation photosensitizers with the most favorable localization for photodynamic therapy of early malignancies in hollow organs.

Topics: Animals; Carcinoma, Squamous Cell; Cricetinae; Mesocricetus; Mesoporphyrins; Microscopy, Fluorescence; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tissue Distribution

New photosensitizing drugs are becoming available which should improve on some of the disadvantages of haematoporphyrin derivates for photodynamic therapy (PDT). The main features are shorter duration of systemic photosensitisation, activation by longer and more penetrating light and better tumour to normal tissue drug uptake ratios. These drugs together with better understanding of in vivo light dosimetry promise to improve both results and clinical acceptability for PDT in future studies.

Topics: Aminolevulinic Acid; Forecasting; Humans; Indoles; Isoindoles; Mesoporphyrins; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Porphyrins; Zinc Compounds