ANTIPROLIFERATIVE ACTIVITY AND PHOTOTOXICITY OF SOME METHYL-DERIVATIVES OF 5-METHOXYPSORALEN AND 5-METHOXYANGELICIN

The in vitro antiproliferative activity and in vivo phototoxicity of s ome methyl derivatives of 5-methoxypsoralen and 5-methoxyangelicin, i. e. 4,4'-dimethyl-5-methoxyangelicin (compound I), 3,4'-dimethyl-5-meth oxyangelicin (compound II), 4,4'-dimethyl-5-methoxypsoralen (compound III); and 3,4'-dimethyl-5-methoxypsoralen (compound IV). have been inv estigated. The effects of the compounds a ere evaluated in vitro on HL 60 and A431 cells, using 5-methoxypsoralen as the reference compound. In both cell lines compound I, II and III showed better antiproliferat ive activity than compound IV and 5-methoxypsoralen. Scanning electron microscopy revealed that all the compounds induced the formation of b lebs and blisters on A431 cell surface. Significant variations in the nuclear area strictly related to the toxicity of the compounds have be en shown in both cell lines. Skin irritancy in vivo was evaluated by m ean of histopathological responses on guinea-pig skin. For each compou nd a damage index was determined by morphometrical analysis of empty s paces in the epidermis. Histopathology revealed skin phototoxicity of compounds which lacked erythemogenic activity by visual scoring. By co upling cytotoxicity data in vitro to skin sensitization ones in vivo, compound I proved a promising candidate for use in clinical trials sin ce due to a high inhibitory effect on the growth of human cell lines c oupled to low skin phototoxicity.