Dofequidar

Dofequidar(MS-209) is a novel quinoline compound, which can reverse P-glycoprotein (P-gp)-mediated MDR.

Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export.[Pubmed:19673889]

Cancer Sci. 2009 Nov;100(11):2060-8.

The ATP-binding cassette (ABC) transporters (ABC-T) actively efflux structurally and mechanistically unrelated anticancer drugs from cells. As a consequence, they can confer multidrug resistance (MDR) to cancer cells. ABC-T are also reported to be phenotypic markers and functional regulators of cancer stem/initiating cells (CSC) and believed to be associated with tumor initiation, progression, and relapse. Dofequidar fumarate, an orally active quinoline compound, has been reported to overcome MDR by inhibiting ABCB1/P-gp, ABCC1/MDR-associated protein 1, or both. Phase III clinical trials suggested that Dofequidar had efficacy in patients who had not received prior therapy. Here we show that Dofequidar inhibits the efflux of chemotherapeutic drugs and increases the sensitivity to anticancer drugs in CSC-like side population (SP) cells isolated from various cancer cell lines. Dofequidar treatment greatly reduced the cell number in the SP fraction. Estimation of ABC-T expression revealed that ABCG2/breast cancer resistance protein (BCRP) mRNA level, but not the ABCB1/P-gp or ABCC1/MDR-associated protein 1 mRNA level, in all the tested SP cells was higher than that in non-SP cells. The in vitro vesicle transporter assay clarified that Dofequidar had the ability to suppress ABCG2/BCRP function. Dofequidar treatment sensitized SP cells to anticancer agents in vitro. We compared the antitumor efficacy of irinotecan (CPT-11) alone with that of CPT-11 plus Dofequidar in xenografted SP cells. Although xenografted SP tumors showed resistance to CPT-11, treatment with CPT-11 plus Dofequidar greatly reduced the SP-derived tumor growth in vivo. Our results suggest the possibility of selective eradication of CSC by inhibiting ABCG2/BCRP.

Dofequidar fumarate (MS-209) in combination with cyclophosphamide, doxorubicin, and fluorouracil for patients with advanced or recurrent breast cancer.[Pubmed:17179098]

J Clin Oncol. 2007 Feb 1;25(4):411-7.

PURPOSE: To evaluate the efficacy and tolerability of Dofequidar plus cyclophosphamide, doxorubicin, and fluorouracil (CAF) therapy in comparison with CAF alone, in patients with advanced or recurrent breast cancer. Dofequidar is a novel, orally active quinoline derivative that reverses multidrug resistance. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled trial, patients were treated with six cycles of CAF therapy: 28 days/cycle, with doxorubicin (25 mg/m2) and fluorouracil (500 mg/m2) administered on days 1 and 8 and cyclophosphamide (100 mg orally [PO]) administered on day 1 through 14. Patients received Dofequidar (900 mg PO) 30 minutes before each dose of doxorubicin. Primary end point was overall response rate (ORR; partial or complete response). In total, 221 patients were assessable. RESULTS: ORR was 42.6% for CAF compared with 53.1% for Dofequidar + CAF, a 24.6% relative improvement and 10.5% absolute increase (P = .077). There was a trend for prolonged progression-free survival (PFS; median 241 days for CAF v 366 days for Dofequidar + CAF; P = .145). In retrospectively defined subgroups, significant improvement in PFS in favor of Dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with Dofequidar did not affect the plasma concentration of doxorubicin. CONCLUSION: Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.