aluminum-tetrasulfophthalocyanine and Pancreatic-Neoplasms

The light-activated drugs AlPcS4 and T4MPyP were studied in a pancreatic carcinoma cell line for their effects on DNA integrity, cell division, proliferation, and survival. The micronucleus assay measured nuclear changes and also the number of actively dividing cells while, under similar conditions, the MTT assay measured cell survival. When tumour cells were exposed to light, pre-treatment with AlPcS4 induced more micronuclei than did T4MPyP at the same levels of cell division and survival. Both drugs showed a correlation between phototoxicity and changes to DNA integrity so establishing micronuclei formation as an important indicator of photodynamic drug action on tumour cells.

Topics: Animals; Carcinoma, Ductal, Breast; Cell Division; Cell Survival; Cricetinae; DNA, Neoplasm; Indoles; Mesocricetus; Micronuclei, Chromosome-Defective; Micronucleus Tests; Organometallic Compounds; Pancreatic Neoplasms; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured

Important differences exist in the responses to photodynamic agents of normal and tumour-derived pancreatic acinar cells. In the present study amylase release has been used to assess the mechanisms by which the photodynamic drugs tetra- and disulphonated aluminium phthalocyanine (A1PcS4, A1PcS2) act on pancreatic cells via energy and calcium-dependent activation and transduction pathways. The photodynamic release of amylase was found to be energy dependent and inhibited by the chelation of free cytoplasmic calcium but not by the removal of extracellular calcium. In contrast to their effects on normal acinar cells, the photodynamic action of A1PcS4 and A1PcS2 was to inhibit amylase secretion from pancreatoma AR4-2J cells. Removal of extracellular calcium reversed this inhibitory effect on AR4-2J cells and produced a significant increase in amylase release, but chelation of free cytoplasmic calcium did not affect the inhibitory photodynamic action of the phthalocyanines on amylase release from the tumour cells. Overall, these results demonstrate further important distinctions between the photodynamic action of sulphonated aluminium phthalocyanines on normal versus tumour exocrine cells of the pancreas and indicate that calcium plays an important role in photodynamic drug action, since these agents affected intracellular calcium mobilisation at some distal point in the membrane signal transduction pathway for regulated secretion. Furthermore, the photodynamic inhibition of constitutive secretion in tumour cells may involve a calcium-dependent membrane target site or modulation of membrane calcium channels by activation of protein kinase C.

Topics: Amylases; Animals; Antimycin A; Bethanechol; Calcium; Carcinoma, Acinar Cell; Deoxyglucose; Egtazic Acid; Indoles; Male; Oligomycins; Organometallic Compounds; Pancreas; Pancreatic Neoplasms; Photochemotherapy; Radiation-Sensitizing Agents; Rats; Rats, Sprague-Dawley; Signal Transduction; Sincalide; Stimulation, Chemical; Tumor Cells, Cultured

The photodynamic effects of sulphonated aluminium phthalocyanine (SALPC) have been compared on cultured AR4-2J cells of a pancreatic carcinoma cell line and on exocrine cells of the normal phenotype freshly isolated from the rat pancreas; a multi-channel perifusion system was used for this kinetic study in vitro. Whereas light alone or SALPC alone was without effect on either cell type, photon activation of cellularly-bound SALPC with light greater than 570 nm permeabilised the cells and caused an increase in amylase secretion from normal acinar cells but a dose-dependent inhibition (10(-7) to 10(-5) M) of amylase release from AR4-2J cells. In contrast, direct permeabilisation of the plasma membrane with digitonin, 10 micrograms ml-1, evoked a marked release of amylase from both types of cell. Elevation of [Ca2+]i by the ionophore A23187, 10(-6) M, elicited secretion of amylase from normal cells but had little effect on AR4-2J cells. Finally, it was established that the differential photodynamic effects of SALPC on amylase release were not attributable to any topographical differences in the microanatomical organisation of normal or tumour-derived cells; furthermore, the structural integrity of normal and AR4-2J cells was maintained after the photodynamic action of SALPC. It is concluded that the generation of singlet oxygen is responsible for permeabilisation of both types of cell and that photon-activated SALPC has functionally distinct effects on the constitutive secretion of amylase of tumour cells and the regulated secretory pathway of normal cells. These observations may be important in the development of drugs with a selective photodynamic action on pancreatic tumour cells.

Topics: Amylases; Animals; Calcimycin; Cell Line; Cell Membrane Permeability; Dexamethasone; Digitonin; Dose-Response Relationship, Drug; Indoles; Organometallic Compounds; Pancreatic Neoplasms; Photochemotherapy; Rats; Tumor Cells, Cultured

Topics: Animals; Brain Neoplasms; Colonic Neoplasms; Cricetinae; Female; Indoles; Male; Mesocricetus; Mice; Organometallic Compounds; Pancreatic Neoplasms; Photochemotherapy; Rats; Rats, Inbred Strains