Circumvention of multidrug resistance by a quinoline derivative, MS-209, in multidrug-resistant human small-cell lung cancer cells and its synergistic interaction with cyclosporin A or verapamil.

Abstract

PURPOSE AND METHODS:

To develop a clinically useful approach to circumvent P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MDR human small-cell lung cancer (SCLC), we examined the ability of a novel quinoline compound, MS-209, to reverse MDR by inhibition of P-gp function in combination with other MDR-reversing drugs using a cytotoxicity assay.

RESULTS:

We established MDR human SCLC cells by culture in medium with gradually increasing concentrations of adriamycin (ADM). Compared with the parental human SCLC cells, SBC-3, the MDR variant SBC-3 cells obtained (SBC-3/ADM) were highly resistant to various chemotherapeutic agents due to P-gp expression. MS-209 reversed the resistance to ADM and vincristine (VCR) of SBC-3/ADM and H69/VP cells in a dose-dependent manner. Moreover, MS-209 in combination with cyclosporin A (CsA) or verapamil (VER) synergistically enhanced the antitumor effects of ADM and VCR on SBC-3/ADM cells. MS-209 restored ADM incorporation and this effect was enhanced by CsA and VER, suggesting that these synergistic effects were due to competitive inhibition of P-gp function.

CONCLUSION:

MS-209 in combination with CsA or VER might increase the efficacy of these chemotherapeutic agents against MDR human SCLC cells.

• Authors: P Shrivastava, M Hanibuchi, S Yano, P Parajuli, T Tsuruo, S Sone
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 42 Issue 6 Pg. 483-90 ( 1998) ISSN: 0344-5704 [Print] Germany
• PMID: 9788575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Quinolines
• dofequidar
• Cyclosporine
• Verapamil

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Small Cell (drug therapy, metabolism, pathology)
• Cyclosporine (pharmacology, therapeutic use)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Synergism
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Quinolines (pharmacology, therapeutic use)
• Tumor Cells, Cultured
• Verapamil (pharmacology, therapeutic use)