We discussed the role of
DNA topoisomerase I (
topo I) inhibitor, which is now widely used in clinical practice, in
cisplatin-resistant
ovarian cancer. Our study showed the synergistic actions between
cisplatin and
7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of 7-ethyl-10-[4-(1-pyperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), in two
cisplatin-resistant
cancer cell lines, HeLa/CDDP and KFr cells, but not in each parent cell line, HeLa and KF cells. Furthermore, HeLa/CDDP cells had a collateral sensitivity to
SN-38. The levels of
topo I
protein in the
cisplatin-resistant cells did not differ from those of their parent cell lines and were unaffected by exposure to
cisplatin. In contrast,
topo I enzymatic activity was 2-4 fold higher in the
cisplatin-resistant cell lines compared with their respective parent cell lines. A significant correlation between the sensitivity for
SN-38 and
topo I activity human clear cell
carcinoma cell lines, which are known as intrinsically ciasplatin-resistant
cancer, was observed. Next, we examined the relationship between
topo I activity and sensitivity to second-line
chemotherapy consisting of
cisplatin and
CPT-11. A total of 30 patients with
ovarian cancer who had initially undergone
chemotherapy consisting of
cisplatin,
doxorubicin, and
cyclophosphamide (CAP) and exhibited measurable lesions were entered in the study.
Tumor samples were obtained in the period between the initial and the second-line
chemotherapy. Of those 30 patients, 18 responded to second-line
chemotherapy and 12 did not.
Topo I activity in
tumor samples of responder was significantly greater than that of in nonresponders. In 8 cases whose samples could be obtained before and after CAP,
topo I activity significantly increased after CAP
therapy. Consequently, the combination
therapy with
cisplatin and
CPT-11 may be effective for patients with
cisplatin-resistant
ovarian cancer. In addition,
topo I enzymatic activity may be a predictor of the sensitivity for
topo I inhibitor.