Fritzer-Szekeres M, Novotny L, Romanova D, Göbl R, Sedlak J, Vachalkova A, Rauko P, Elford H L, Szekeres T
Clinical Institute for Medical and Chemical Laboratory Diagnostics, Vienna, Austria.
Life Sci. 1998;63(7):545-52. doi: 10.1016/s0024-3205(98)00305-1.
Ribonucleotide reductase is the rate limiting enzyme of de novo DNA synthesis; its activity is significantly increased in tumor cells related to the proliferation rate. Therefore the enzyme is considered to be an excellent target for cancer chemotherapy. In the present study we tested the in vitro and in vivo antitumor effects of a drug combination using trimidox (3,4,5-trihydroxybenzamidoxime), a novel inhibitor of ribonucleotide reductase with adriamycin, a widely used anticancer drug. This combination was selected because adriamycin generates free radicals being responsible for cardiotoxic side effects; trimidox has been shown to be a good free radical scavenger. The in vitro cytotoxic effect of the drug combination was examined in L1210 mouse leukemia cells employing a MTT chemosensitivity assay. Incubation of these cells with adriamycin and trimidox together yielded less than additive cytotoxic effects compared to either drug alone. These effects were not caused by the involvement of p-glycoprotein mediated drug efflux. However, when the effect of trimidox and adriamycin in combination was examined in L1210 leukemia bearing mice antitumor effects of adriamycin could be enhanced by the presence of trimidox. Our data indicate, that the in vivo combination of adriamycin together with trimidox might be beneficial for the treatment of malignancies.
核糖核苷酸还原酶是从头合成DNA的限速酶；其活性在与增殖速率相关的肿瘤细胞中显著增加。因此，该酶被认为是癌症化疗的一个极佳靶点。在本研究中，我们测试了一种药物组合的体外和体内抗肿瘤作用，该组合使用了新型核糖核苷酸还原酶抑制剂三甲氧苄二氨嘧啶（3,4,5-三羟基苯甲脒肟）与广泛使用的抗癌药物阿霉素。选择这种组合是因为阿霉素会产生导致心脏毒性副作用的自由基；三甲氧苄二氨嘧啶已被证明是一种良好的自由基清除剂。采用MTT化学敏感性测定法在L1210小鼠白血病细胞中检测了该药物组合的体外细胞毒性作用。与单独使用任何一种药物相比，将这些细胞与阿霉素和三甲氧苄二氨嘧啶一起孵育产生的细胞毒性作用小于相加效应。这些效应不是由P-糖蛋白介导的药物外排所导致。然而，当在荷L1210白血病小鼠中检测三甲氧苄二氨嘧啶和阿霉素联合使用的效果时，三甲氧苄二氨嘧啶的存在可增强阿霉素的抗肿瘤作用。我们的数据表明，阿霉素与三甲氧苄二氨嘧啶的体内联合使用可能对恶性肿瘤的治疗有益。
