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

Autor: Setsuko Imagawa, Akiko Tohgo, Michio Iwahana, Ikuo Mitsui, Megumi Minami, Mineko Ishii, Akio Ejima
Rok vydání: 2000
Předmět:
Cancer Research
ATP Binding Cassette Transporter
Subfamily B
Lung Neoplasms
Blotting
Western
In Vitro Techniques
chemistry.chemical_compound
Drug Stability
In vivo
Tubulin
medicine
Tumor Cells
Cultured
Cytotoxic T cell
ATP Binding Cassette Transporter
Subfamily G
Member 2
Humans
Pharmacology (medical)
Carcinoma
Small Cell
DNA Primers
Glutathione Transferase
Pharmacology
Mitoxantrone
biology
Chemistry
Reverse Transcriptase Polymerase Chain Reaction
Topoisomerase
Antineoplastic Agents
Phytogenic
Glutathione
Drug Resistance
Multiple
Tubulin Modulators
Neoplasm Proteins
Isoenzymes
Oncology
Paclitaxel
DNA Topoisomerases
Type I
Glutathione S-Transferase pi
Cell culture
Drug Resistance
Neoplasm
Inactivation
Metabolic
biology.protein
Cancer research
Topotecan
ATP-Binding Cassette Transporters
Camptothecin
Fluorouracil
Cisplatin
Topoisomerase I Inhibitors
medicine.drug
Zdroj: Anti-cancer drugs. 11(5)
ISSN: 0959-4973
Popis: 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.
Databáze: OpenAIRE
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