Abstract | PURPOSE 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.
|
Authors | F 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 |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 40
Issue 5
Pg. 425-32
( 1997)
ISSN: 0344-5704 [Print] Germany |
PMID | 9272120
(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)
|