ALTERATIONS OF MELANIN SYNTHESIS IN HUMAN-MELANOMA CELLS SELECTED IN-VITRO FOR MULTIDRUG-RESISTANCE

Previous data showing the correlation of multidrug resistance (MDR) an d differentiation in tumor cell populations (MELLONI et al. 1988; STAV ROVSKAYA et al. 1990) suggest that: 1) isolation of MDR cells by cytos tatic drugs leads to the selection of more differentiated cell variant s and 2) in more differentiated cell variants the activity of MDR-rela ted P-glycoprotein (Pgp) is more prominent than in less differentiated cells. Here we used human melanoma cell line mS and two variants sele cted from mS population: a) MDR variant of mS selected by colchicine ( mS-0.5) and b) mS-trRAR/2 - variant obtained by introduction of expres sing retinoic acid receptor RAR-alpha cDNA into mS cell. The different iation status, expression of MDR 1 gene and Pgp functioning were compa red in wild-type cells and mS variants. Electron microscopic examinati on of melanosomes showed that the mS-0.5 subline comprised more differ entiating cells in the population than parental mS cultures and that t hese cells were at later stages of melanogenesis. The increase in the degree of differentiation in mS-0.5 population coincided with MDR1 gen e overexpression, occurrence of Pgp molecules on the cell membrane and acceleration of Pgp-mediated Rhodamine 123 (Rh123) efflux. mS-trRAR/2 , proved to be more differentiated than mS cells. The MDR1 mRNA level and Rh123 efflux were not elevated in mS-trRAR/2 cells, however, retin oic acid (RA) treatment increased both the degree of differentiation a nd Rh123 efflux in mS-trRAR/2 to a greater extent than in mS cultures. Thus, the data obtained in this study are in favor of the supposition s mentioned above. The mechanisms of coordinated alterations of differ entiation and Pgp activity in MDR cells are discussed.