Bcl-2 gene prevents induction of apoptosis in l1210 murine leukemia-cells by sn-38, a metabolite of the camptothecin derivative cpt-11.

New camptothecin (CPT) derivatives have recently been synthesized following the finding that CPT has strong antitumor activity due to its inhibition of topoisomerase I through the formation of stable topoisomerase I-DNA cleavable complexes, but has not been clinically used due to its pronounced toxicity. 7-ethyl-10-hydroxy-CPT (SN-38), a metabolite of the CPT derivative 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-CPT(CPT-11), plays an essential role in mediating the antitumor effect of CPT-11. However, the reasons for the cytotoxicity of SN-38 remain unclear. In this study, we demonstrated using results of DNA fragmentation assay and cell cycle analysis that SN-38 and CPT both induce apoptosis in L1210 murine leukemia cells. We demonstrated in addition that enforced expression of the bcl-2 gene in L1210 cells by MPZenNeo (bcl-2) retroviral gene transfer increased resistance to the apoptosis induced by SN-38 and CPT. These findings suggest the possibility that the bcl-2 gene impedes the activity of a common pathway for apoptosis induced by SN-38 and CPT.