DEFICIENT APOPTOTIC PROCESS IN CISPLATIN-RESISTANT L1210 CELLS CANNOTACCOUNT FOR THE CELLULAR-RESPONSE TO VARIOUS DRUG TREATMENTS

Apoptosis is a major determinant of the effectiveness of antitumor che motherapy since most of the drugs used in cancer treatment provoke cel l death by this process. We selected L1210/0.7R (7-fold) and L1210/3R (16-fold) murine leukemia cells resistant to cisplatin (CDDP) by adapt ation of parental L1210/S cells to increasing drug concentration. L121 0/0.7R exhibited a decreased apoptosis response to CDDP compared to pa rental L1210/S, while it was totally defective in L1210/3R as analyzed by cell morphology, DNA fragmentation, and poly(ADP-ribose) polymeras e cleavage. This default in apoptosis did not result from differential expression of the antiapoptotic protein bcl-2 or from altered express ion of p53. L1210/3R was resistant to other cross-linking agents and s ensitive to topoisomerase II inhibitors and microtubule poisons. Whate ver the drug sensitivity phenotype to these agents, L1210/3R was total ly defective in apoptosis in response to drug treatment, showing that apoptosis control cannot be directly involved in the resistance proces s of these cell lines. (C) 1997 Academic Press.