Nishiyama M, Suzuki K, Kumazaki T, Yamamoto W, Toge T, Okamura T, Kurisu K
Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
Int J Cancer. 1997 Aug 7;72(4):649-56. doi: 10.1002/(sici)1097-0215(19970807)72:4<649::aid-ijc17>3.0.co;2-6.
In 10 human cancer cell lines, the activity of mitomycin C (MMC) was found to be determined by an interplay between activation by DT-diaphorase (DTD) and inactivation by glutathione S-transferase (GST). NADPH/cytochrome P-450 reductase was not responsible for MMC activation and expression of MDRI (Mr 170,000 P-glycoprotein), and MRP (multidrug resistance-associated protein) genes did not relate to MMC resistance. Gene expression analysis for NQO1 (DTD gene) and GSTpi predicted which enzyme activity predominated in a cell line, except K562 and K562/DOX. For tumors with DTD activity only, MMC given by itself was most active. In cell lines in which DTD action was predominant, tumor selectivity was achieved by enhancing DTD-mediated activation with m-iodobenzylguanidine and hyperglycemia, which reduced the intra-tumoral pH. KW2149, a novel MMC analogue activated by glutathione, was most active against tumors in which GSTpi predominated. These various enzyme-specific effects could be observed even in cell lines derived from tumors with multidrug resistance. Such MMC treatment based on cell enzymology may enhance significantly MMC efficacy, helping to overcome multidrug resistance.
在10种人类癌细胞系中，发现丝裂霉素C（MMC）的活性由DT-黄递酶（DTD）的激活作用与谷胱甘肽S-转移酶（GST）的失活作用之间的相互作用决定。NADPH/细胞色素P-450还原酶不负责MMC的激活，多药耐药蛋白1（Mr 170,000 P-糖蛋白）和多药耐药相关蛋白（MRP）基因的表达与MMC耐药性无关。对NQO1（DTD基因）和GSTpi进行基因表达分析，可以预测除K562和K562/DOX外，哪种酶活性在某一细胞系中占主导地位。对于仅具有DTD活性的肿瘤，单独给予MMC时活性最高。在DTD作用占主导的细胞系中，通过用间碘苄胍增强DTD介导的激活作用和高血糖症（可降低肿瘤内pH值）来实现肿瘤选择性。KW2149是一种新型的由谷胱甘肽激活的MMC类似物，对GSTpi占主导的肿瘤活性最高。即使在源自多药耐药肿瘤的细胞系中也能观察到这些各种酶特异性效应。这种基于细胞酶学的MMC治疗可能会显著提高MMC的疗效，有助于克服多药耐药性。
