Dofequidar(MS-209) is a novel quinoline compound, which can reverse P-glycoprotein (P-gp)-mediated MDR. In cell-based studies, MS-209 at 3 μM successfully mitigated docetaxel resistance in MDR cancer cells, maintaining this concentration in blood plasma for over 7 hours without significant toxicity[1]. MS-209 reinstates the sensitivity of SBC-3 / ADM cells to VP-16, ADM, and VCR in a dose-dependent manner[2]. MS-209 significantly reverses resistance to adriamycin (ADM) and vincristine (VCR) in established MDR tumor cell lines, such as 2780AD and KB-C1, and enhances the cytotoxic effects of ADM and VCR on a variety of human and mouse cell lines. Notably, in 4-1St cells, which show high resistance to ADM and VCR, a 3 μM concentration of MS-209 boosts the cytotoxicity of ADM and VCR by 88 and 350 times, respectively. Administering docetaxel at its maximal tolerated dose (MTD) demonstrated noticeable antitumor effects on HCT-15 tumor xenografts, known for their intrinsic resistance, with MS-209 further enhancing docetaxel's antitumor efficacy. In the case of MCF-7/ADM tumor xenografts, which express higher levels of P-gp, docetaxel alone at the MTD failed to exhibit antitumor effects. However, when combined with MS-209, the MTD of docetaxel significantly inhibited the growth of MCF-7/ADM tumors[1]. Intravenous injection of SBC-3 or SBC-3/ADM cells into severe combined immunodeficiency (SCID) mice, depleted of natural killer (NK) cells, resulted in metastatic colonies forming in the liver, kidneys, and lymph nodes, with SBC-3/ADM cells leading to quicker metastasis than SBC-3 cells. While VP-16 and ADM treatments reduced metastasis from SBC-3 cells, they did not affect metastasis from SBC-3/ADM cells. Although MS-209 alone did not impact metastasis from either cell type, its combination with VP-16 or ADM significantly reduced metastatic spread of SBC-3/ADM cells to various organs[2]. Oral administration of MS-209 along with ADM substantially increased the antitumor effects of ADM on Colon 26 and 4-1St tumors implanted subcutaneously in mice, surpassing the antitumor efficacy of ADM alone at its MTD[3].
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