Establishment of a CPT-11-resistant human ovarian cancer cell line.
A camptothecin analog, ((4s)-4,11-diethyl-4-hydroxy-9-[(4- piperidinopiperidino)carbonyloxy]dione hydrochloride trihydrate), (CPT-11), is a recently developed topoisomerase I (Topo I) inhibitor which attracts the attention of clinicians because of its high antitumor activity. We established a CPT-11-resistant human ovarian cell line, HAC2/ CPT, from the parental HAC2 cell line. An in vitro drug sensitivity assay revealed that HAC2/ CPT was 9.7 and 4.7 times as resistant as HAC2 to CPT-11 and 7-ethyl-10-hydroxy-CPT-11 (SN-38), an active metabolite of CPT-11, respectively. HAC2/ CPT showed no cross-resistance to other drugs tested (adriamycin, etoposide, cisplatin and Taxol), suggesting that HAC2/ CPT acquired a phenotype specifically resistant to the Topo I inhibitor. In order to elucidate the mechanism of the resistance, we measured Topo I activity of HAC2 and HAC2/ CPT. The activity of Topo I of HAC2/ CPT was reduced to half of that of the parental HAC2 cells. To determine the cause of the decreased activity of Topo I, the mutation of the Topo I gene was searched for by the polymerase chain reaction and the reverse transcriptase analysis. Topo I gene mutation was not detected. The amount of Topo I protein was measured by immunoblotting and a marked decrease of Topo I protein was observed in HAC2/ CPT. These results suggest that the decreased protein content of Topo I causes the decreased activity of Topo I and the decreased sensitivity of HAC2/ CPT to Topo I inhibitors.[1]References
- Establishment of a CPT-11-resistant human ovarian cancer cell line. Kijima, T., Kubota, N., Nishio, K. Anticancer Res. (1994) [Pubmed]
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