[Quantitative analysis of DNA topoisomerase I activity in human and rat glioma: characterization and mechanism of resistance to antitopoisomerase chemical, camptothecin-11].

Abstract

Camptothecin-11 (CPT-11) is a new derivation of camptothecin, a plant alkaloid antitumor agent. Previous studies indicated that antitumor activity of CPT-11 was mediated through interaction of the drugs with its target enzyme, DNA topoisomerase I (topo I). In this study, we studied the relation between sensitivity to CPT-11 and topo I activity of glioma cells. Furthermore, we established CPT-11 resistant cell lines in order to elucidate potential mechanisms of drug resistance. A clear correlation between the sensitivities to CPT-11 and topo I activities in surgical glioma specimens was demonstrated. Activities of topo I in CPT-11 sensitive group (IC50 values for CPT-11; < 50 micrograms/ml) tended to be higher than those in CPT-11 resistant group (IC50 values; > or = 50). Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors. CPT-11 resistance cell lines (T98G/CPT-11 and C6) respectively exhibit a 5.4- and 7.3-fold increase in resistance to CPT-11. No differences in topo I activity and intracellular accumulation of CPT-11 were observed between parent and CPT-11 resistant lines. On the other hand, topo I from T98G/CPT-11 and C6/CPT-11 cells were at least 4- and 2-fold resistant to the inhibitory effect of the CPT-11 on the relaxation activity of topo I in comparison with their parent lines. This enzymological difference may be responsible for the resistance to CPT-11.