Quantitative analysis of DNA topoisomerase I activity in human and rat glioma: Characterization and mechanism of resistance to antitopoisomerase chemical, camptothecin-11
✍ Scribed by Dr. Yoshihito Matsumoto; Takashi Fujiwara; Yasumasa Honjo; Noboru Sasaoka; Takahiro Tsuchida; Seigo Nagao
- Publisher
- John Wiley and Sons
- Year
- 1993
- Tongue
- English
- Weight
- 664 KB
- Volume
- 53
- Category
- Article
- ISSN
- 0022-4790
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✦ Synopsis
Camptothecin-1 1 (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 top0 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-1 1 and top0 I activities in surgical glioma specimens was demonstrated. Activities of top0 I in the CPT-1 l-sensitive group (I& values for CPT-11; <50 pg/ml) tended to be higher than those in the CPT-1 l-resistant group (IC50 values, 250). Top0 I activity may serve as a novel marker to predict the sensitivity of gliomas to top0 inhibitors. CPT-1 l-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 top0 I activity and intracellular accumulation of CPT-1 1 were observed between the parent and CPT-1 l-resistant lines. On the other hand, top0 I from T98G/CPT-11 and C6-CPT-1 1 cells was at least 4-and 2-fold resistant to the inhibitory effect of the CPT-11 on the relaxation activity of top0 I, in comparison with their parent lines. This enzymological difference may be responsible for the resistance to