|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1995 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1994 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Multidrug resistance is a major obstacle in cancer chemotherapy. To obtain potent multidrug resistance modulators we synthesized a series of diamine, dicarboxamide, and disulfonamide compounds with terminal benzene, methyl- or chloro-substituted benzene rings at both termini and examined the effect on vinblastine accumulation in multidrug-resistant mouse leukemia P388/ADR cells. The efficacy of these compounds was generally in the order of disulfonamides>diamines>dicarboxamides. N-Methylated diamine and disulfonamide compounds having terminal methyl- or chloro-substituted benzene ring in their structure also showed rather potent efficacy. From these findings, we synthesized a novel disulfonamide compound, 1,2,3,4,5,6-hexahydro-2,5-bis (p-toluenesulfonyl) benzo [2,5] diazicine, and this compound potently reversed multidrug-resistance in vitro. Furthermore, 1,3,5-triazacycloheptanes were synthesized and examined for reversal of P-glycoprotein-dependent multidrug resistance. Most of these compounds increased the intracellular uptake of vinblastine in multidrug-resistant mouse leukemia P388/ADR cells without influence upon the vinblastine accumulation in P388/S cells. The efficacy of 1,5-dibenzyl-1,3,5-triazacycloheptanes in increasing the vinblastine accumulation was in the order of 2,4-dithioxo>2-oxo-4-thioxo=4- (methylthio) -2oxo>2,4-dioxo. The efficacy was further increased when the benzyl group was converted to a chlorobenzyl group. Among these compounds, 1,5-bis (4-chlorobenzyl) -1,5,6,7-tetrahydro-4-methylthio ) -2H-1,3,5-triazepin-2-one increased the in vitro cell growth-inhibitory effect of vinblastine, adriamycin, and mitomycin C on P388/ADR cells and prolonged the life span of P388/ADR-bearing mice in combined therapy with vinblastine more than vinblastine alone.