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A novel quinoline derivative, MS-209, overcomes drug resistance of human lung cancer cells expressing the multidrug resistance-associated protein (MRP) gene.

AbstractPURPOSE AND METHODS:
MS-209 is a newly synthesized quinoline compound used orally to overcome human P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). The multidrug resistance-associated protein (MRP) gene is thought to play an important role in MDR in lung cancer. To investigate whether MS-209 could also overcome MRP-mediated MDR, we examined the effect of the compound using a cytotoxicity assay on MDR1 gene-negative drug-selected MDR and wildtype lung cancer cells with various levels of MRP gene expression. The effects of MS-209 were compared with those of verapamil (VER) and cyclosporin A (CsA). The level of MRP gene expression in the cells was evaluated semiquantitatively by RT-PCR. For vincristine (VCR), intracellular accumulation of [3H]-VCR was measured with or without MS-209.
RESULTS:
In MDR UMCC-1/VP small-cell lung carcinoma cell line, 5 microM of MS-209 and VER enhanced the cytotoxicity of etoposide, doxorubicin (DOX) and VCR more than twofold, and completely reversed the resistance to VCR. The mean reversing effects of MS-209 on DOX and VCR were significantly stronger than those of VER and CsA. In wildtype non-small-cell lung carcinoma cells, the effects of MS-209 were almost equal to those of VER and CsA. The effect of these three agents correlated with the level of MRP gene expression. The MS-209-induced increase in intracellular accumulation of VCR was proportional to the level of MRP gene expression in these cells.
CONCLUSION:
Our results indicate that MS-209 is a potentially useful drug that can overcome MRP-mediated intrinsic and acquired MDR in human lung cancer.
AuthorsF Narasaki, M Oka, M Fukuda, R Nakano, K Ikeda, H Takatani, K Terashi, H Soda, O Yano, T Nakamura, L A Doyle, T Tsuruo, S Kohno
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 40 Issue 5 Pg. 425-32 ( 1997) ISSN: 0344-5704 [Print] Germany
PMID9272120 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Quinolines
  • dofequidar
Topics
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Carcinoma, Small Cell (drug therapy, physiopathology)
  • Drug Resistance, Neoplasm (genetics)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • HL-60 Cells (drug effects)
  • Humans
  • Lung Neoplasms (drug therapy, physiopathology)
  • Quinolines (pharmacology, therapeutic use)
  • Tumor Cells, Cultured (drug effects)

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