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 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 the 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 the CPT-11-sensitive group (IC50 values for CPT-11; < 50 micrograms/ml) tended to be higher than those in the 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-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, topo I from T98G/CPT-11 and C6-CPT-11 cells was 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.
Matsumoto
Y
Y
Department of Neurological Surgery, Kagawa Medical School, Japan.
Fujiwara
T
T
Honjo
Y
Y
Sasaoka
N
N
Tsuchida
T
T
Nagao
S
S
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004351:Drug Resistance; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D000077146:Irinotecan; D051381:Rats; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin