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

Anticancer Drugs. 2000 Jun;11(5):353-62. doi: 10.1097/00001813-200006000-00005.

Abstract

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Blotting, Western
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology*
  • Carcinoma, Small Cell / drug therapy*
  • Carcinoma, Small Cell / metabolism
  • Cisplatin / pharmacology
  • DNA Primers / chemistry
  • DNA Topoisomerases, Type I / metabolism
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Drug Stability
  • Fluorouracil / pharmacology
  • Glutathione / metabolism
  • Glutathione S-Transferase pi
  • Glutathione Transferase / metabolism
  • Humans
  • In Vitro Techniques
  • Inactivation, Metabolic
  • Isoenzymes / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Neoplasm Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Topoisomerase I Inhibitors
  • Tubulin / metabolism
  • Tubulin Modulators
  • Tumor Cells, Cultured / drug effects*

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents, Phytogenic
  • DNA Primers
  • Isoenzymes
  • Neoplasm Proteins
  • Topoisomerase I Inhibitors
  • Tubulin
  • Tubulin Modulators
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • Glutathione Transferase
  • DNA Topoisomerases, Type I
  • Glutathione
  • exatecan
  • Cisplatin
  • Fluorouracil
  • Camptothecin