Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6.
DX-8951f, a new water-soluble camptothecin (CPT) derivative, has been reported to show potent antitumor effects against various tumors in vitro and in vivo. We further evaluated the cytotoxic effect of DX-8951f against eight drug-resistant sublines derived by stepwise exposure of human oat cell carcinoma PC-6 to various drugs. In paclitaxel-, adriamycin-, vincristine- and etoposide-resistant cells, overexpression of P-glycoprotein (P-gp) and a correlative reduction in drug accumulation and typical drug-sensitivity pattern were confirmed. The etoposide-resistant line with the highest P-gp level was cross-resistant also to SN-38, CPT-11 and topotecan (TPT), but not to 9-aminocamptothecin (9-AC), CPT and DX-8951f. SN-38- and CPT-11-resistant cells, of which topoisomerase I activities and levels were similar to those of the parent cells, showed cross-resistance clearly to TPT, 9-AC and mitoxantrone, but hardly to DX-8951f. In these two resistant sublines, the intracellular topotecan level was significantly lower than that in parental PC-6 and the reduced accumulation was found to be mediated by breast cancer resistant protein (BCRP). The cisplatin-resistant variant, which had a 2-fold increase in glutathione content, showed no cross-resistance and the 5-fluorouracil-resistant variant, which had a 50% decrease in glutathione content, exhibited collateral sensitivity to most of the other anticancer agents including DX-8951f. We concluded that DX-8951f showed a potent cytotoxic effect on various types of drug-resistant cells.
Ishii
M
M
New Product Research Laboratories IV, Daiichi Pharmaceutical Co, Ltd, Tokyo R&D Center, Tokyo, Japan.
Iwahana
M
M
Mitsui
I
I
Minami
M
M
Imagawa
S
S
Tohgo
A
A
Ejima
A
A
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004355:Drug Stability; D005472:Fluorouracil / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059004:Topoisomerase I Inhibitors; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured / Q000187:drug effects*
C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D007527:Isoenzymes; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D014404:Tubulin; D050257:Tubulin Modulators; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D004264:DNA Topoisomerases, Type I; D005978:Glutathione; C095887:exatecan; D002945:Cisplatin; D005472:Fluorouracil; D002166:Camptothecin