POTENTIATION OF THE ANTITUMOR-ACTIVITY BY A NOVEL QUINOLINE COMPOUND,MS-209, IN MULTIDRUG-RESISTANT SOLID TUMOR-CELL LINES

A novel quinoline compound, MS-209, was examined for its ability to re verse multidrug resistance (MDR) in several murine and human MDR solid tumor cell lines both in vitro and in vivo. MS-209 strongly reversed drug resistance to adriamycin (ADM) and vincristine (VCR) in acquired MDR tumor cell lines, 2780AD and KB-C1. In addition, MS-209 enhanced t he cytotoxic effect of ADM and VCR on various human and murine cell li nes. Particularly in 4-1St cells, which are extremely resistant to ADM and VCR, MS-209 at a concentration of 3 mu M enhanced the cytotoxicit y of ADM and VCR, 88- and 350-fold, respectively. MS-209 administered orally, together with ADM, enhanced the antitumor activity of ADM on C olon 26 and 4-1St tumors implanted subcutaneously (SC) in mice; the an titumor effect of ADM plus MS-209 was higher than that of ADM alone at the maximum tolerated dose (MTD). Furthermore, the coadministration s chedules of MS-209 to attain the highest potentiation of ADM activity were examined using Colon 26 tumors. The maximum antitumor activity wa s obtained when MS-209 was administered on the same day as ADM. MS-209 administered a day before the ADM injection exhibited no potentiation effect, whereas MS-209 administered a day after the ADM injection sho wed a moderate effect. The effect of MS-209 was weaker when administer ed in a fractionated manner than when administered as a single dose. T he results presented in this article suggest that MS-209 is an effecti ve agent to overcome MDR in cancer chemotherapy.