ENHANCEMENT OF MELPHALAN TOXICITY BY OCTANOL IN OVARIAN ADENOCARCINOMA CELL-LINES - EFFECTS OF ALTERED CELL-CELL COMMUNICATION, GLUTATHIONELEVELS, AND PLASMA-MEMBRANE FLUIDITY

A2780 and COLO-316 ovarian adenocarcinoma cell lines were exposed to 1 .0 mM 1-octanol for 12 hr in order to evaluate the potential effects o f inhibition of gap junction-mediated intercellular communication (GJI C) on cellular responses to the chemotherapeutic drug melphalan. Other cellular endpoints relevant to drug-resistance mechanisms which were monitored after treatments included cellular glutathione levels, gluta thione 5-transferase activity, mitochondrial membrane potential, and p lasma membrane lipid mobility. In cells which were sensitive to melpha lan, octanol enhanced melphalan toxicity in the GJIC-competent (A2780/ 5) but not GJIC-incompetent (COLO-316/S) sensitive cells. Although oct anol increases plasma membrane lipid mobility in A2780/5 and COLO-316/ S, it appears that enhancement of A2780/S sensitivity to melphalan may be due to inhibition of GJIC. In melphalan-resistant cells (A2780/R a nd COLO-316/R), 1.0 mM octanol treatment for 12 hr combined with melph alan reversed the resistance of the cells to the drug. Therefore, alte rations in cellular glutathione metabolism and effects on the plasma m embrane in addition to uncoupling of GJIC may be involved in sensitizi ng communication-competent and communication-incompetent resistant cel ls because COLO-316/R lacks gap junction-mediated intercellular commun ication. Further, analysis of mitochondrial membrane potential provide d an index of acquired drug resistance and the efficacy of melphalan a nd combined octanol/melphalan toxicity. (C) 1995 Society of Toxicology .