QUANTITATIVE-ANALYSIS OF DNA TOPOISOMERASE-I ACTIVITY IN HUMAN AND RAT GLIOMA - CHARACTERIZATION AND MECHANISM OF RESISTANCE TO ANTITOPOISOMERASE CHEMICAL, CAMPTOTHECIN-11

Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent. Previous studies indicated that antitumor ac tivity of CPT-11 was mediated through interaction of the drugs with it s target enzyme, DNA topoisomerase I (topo I). In this study, we studi ed the relation between sensitivity to CPT-11 and topo I activity of g lioma cells. Furthermore, we established CPT-11 resistant cell lines i n order to elucidate the potential mechanisms of drug resistance. A cl ear correlation between the sensitivities to CPT-11 and topo I activit ies in surgical glioma specimens was demonstrated. Activities of topo I in the CPT-11-sensitive group (IC50 values for CPT-11; <50 mug/ml) t ended to be higher than those in the CPT-11-resistant group (IC50 valu es, greater-than-or-equal-to 50). Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors. CPT- 11-resistant 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 the parent and CPT-11-resistant lines. On the other hand, top o I from T98G/CPT-11 and C6-CPT-11 cells was at least 4- and 2-fold re sistant to the inhibitory effect of the CPT-11 on the relaxation activ ity of topo I, in comparison with their parent lines. This enzymologic al difference may be responsible for the resistance to CPT-11.