Genne P, Dimanche-Boitrel M T, Mauvernay R Y, Gutierrez G, Duchamp O, Petit J M, Martin F, Chauffert B
Research Group on Digestive Tumors, INSERM U.252, Faculty of Medicine, University of Dijon, France.
Cancer Res. 1992 May 15;52(10):2797-801.
Circumvention of multidrug resistance is a new field of investigation in cancer chemotherapy, and safe and potent multidrug resistance inhibitors are needed for clinical use. We investigated several analogues of quinine for their ability to increase anthracycline uptake in resistant cancer cells. Cinchonine was the most potent inhibitor of anthracycline resistance in vitro, and its activity was little altered by serum proteins. Serum from rats treated with i.v. cinchonine produced greater uptake of doxorubicin in cancer cells (DHD/K12/PROb rat colon cells and K562/ADM human leukemic cells) than did serum from quinine-treated rats (ex vivo assay). Cinchonine was more effective than quinine in reducing tumor mass and increasing the survival of rats inoculated i.p. with DHD/K12/PROb cells and treated i.p. with deoxydoxorubicin. Moreover, the acute toxicity of cinchonine in rats and mice was lower than that of other quinine-related compounds. The lower toxicity and greater potentiation of in vivo anthracycline activity produced by cinchonine are favorable characteristics for its use as an anti-multidrug resistance agent in future clinical trials.
克服多药耐药性是癌症化疗研究的一个新领域，临床应用需要安全有效的多药耐药抑制剂。我们研究了几种奎宁类似物增加耐药癌细胞摄取蒽环类药物的能力。辛可宁是体外最有效的蒽环类耐药抑制剂，其活性受血清蛋白影响较小。静脉注射辛可宁处理的大鼠血清比奎宁处理的大鼠血清能使癌细胞（DHD/K12/PROb大鼠结肠癌细胞和K562/ADM人白血病细胞）摄取更多的阿霉素（体外试验）。在减少接种DHD/K12/PROb细胞并腹腔注射脱氧阿霉素的大鼠肿瘤质量和提高其生存率方面，辛可宁比奎宁更有效。此外，辛可宁对大鼠和小鼠的急性毒性低于其他奎宁相关化合物。辛可宁较低的毒性和对体内蒽环类药物活性的更强增强作用是其在未来临床试验中用作抗多药耐药剂的有利特性。
