INDUCTION OF APOPTOSIS IN MULTIDRUG-RESISTANT (MDR) HUMAN GLIOBLASTOMA CELLS BY SN-38, A METABOLITE OF THE CAMPTOTHECIN DERIVATIVE CPT-11

The overexpression of the multidrug resistance (mdr 1) gene and its pr oduct, P-glycoprotein (P-gp), is thought to limit the successful chemo therapy of human tumors. Recent studies demonstrate that SN-38, a meta bolite of the camptothecin (CPT) derivative CPT-11, has antitumor effe cts on several tumors, but the mechanisms responsible for its cytotoxi city remain unclear. We therefore determined whether SN-38 has cytotox ic effects on MDR human glioblastoma GB-1 cells and non-MDR human glio blastoma U87-MG cells. Furthermore, we determined what role SN-38 play s in the induction of cytotoxicity in these tumor cells. In this study , we demonstrated that SN-38 had significantly stronger antirumor effe cts on GB-1 and U-87MG cells than did CPT (P < 0.01 and P < 0.05, resp ectively). In addition, findings obtained using a DNA fragmentation as say, Hoechst 33258 staining, in situ end-labeling and cell cycle analy sis demonstrated that SN-38 induced apoptosis in these tumors. Our res ults suggest that SN-38 has a stronger antitumor effect on malignant g lioma cells regardless of MDR expression than does CPT, and therefore can be considered a new chemotherapeutic agent potentially effective i n the treatment of human primary or recurrent malignant gliomas resist ant to chemotherapy.