P-GLYCOPROTEIN OVEREXPRESSION IN MOUSE CELLS DOES NOT CORRELATE WITH RESISTANCE TO N-BENZYLADRIAMYCIN-14-VALERATE (AD-198)

The novel anthracycline N-benzyladriamycin-1 4-valerate (AD 198) circu mvents P-glycoprotein (P-gp)- and altered topoisomerase II-mediated dr ug resistance. Nevertheless, AD 198-resistant (AD 198(R)) murine J774. 2 cells overexpressed P-gp, were cross-resistant to other drugs throug h reduced accumulation and were rendered sensitive by continuous expos ure to verapamil. Intracellular AD 198 was, however, similar in sensit ive and resistant cells, Consequently, the ability of P-gp to confer A D 198 resistance was examined. It was observed that (i) AD 198 resista nce in AD 198(R) cells grown without drug for 15 months declined by 60 % with only a 10-15% loss of vinblastine cross-resistance and P-gp exp ression; (ii) a cloned AD 198(R) P388 mouse leukemic cell line did not express P-gp; and (iii) verapamil did not attenuate resistance agains t high-dose, short-term exposure to AD 198. Therefore, AD 198 resistan ce appeared to be P-gp-independent despite P-gp overexpression. Antiox idant enzyme and topoisomerase II activities remained unchanged betwee n sensitive and resistant cells. These results suggest that AD 198 res istance was conferred by a novel mechanism.