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Quantitative analysis of DNA topoisomerase I activity in human and rat glioma: Characterization and mechanism of resistance to antitopoisomerase chemical, camptothecin‐11
Author(s) -
Matsumoto Yoshihito,
Fujiwara Takashi,
Honjo Yasumasa,
Sasaoka Noboru,
Tsuchida Takahiro,
Nagao Seigo
Publication year - 1993
Publication title -
journal of surgical oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.201
H-Index - 111
eISSN - 1096-9098
pISSN - 0022-4790
DOI - 10.1002/jso.2930530210
Subject(s) - camptothecin , topoisomerase , alkaloid , glioma , cell culture , mechanism of action , intracellular , pharmacology , enzyme , biology , microbiology and biotechnology , medicine , biochemistry , in vitro , stereochemistry , chemistry , cancer research , genetics
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 (IC 50 values for CPT‐11; <50 μg/ml) tended to be higher than those in the CPT‐11‐resistant group (IC 50 values, ≥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. © 1993 Wiley‐Liss, Inc.