S. Nakatsu et al., INDUCTION OF APOPTOSIS IN MULTIDRUG-RESISTANT (MDR) HUMAN GLIOBLASTOMA CELLS BY SN-38, A METABOLITE OF THE CAMPTOTHECIN DERIVATIVE CPT-11, Cancer chemotherapy and pharmacology, 39(5), 1997, pp. 417-423
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.