Natsumeda Y, Lui M S, Emrani J, Faderan M A, Reardon M A, Eble J N, Glover J L, Weber G
Cancer Res. 1985 Jun;45(6):2556-9.
The purpose of this study was to elucidate the purine enzymic programs of human primary colorectal carcinomas. Marked alteration in the enzymology of the human colon neoplasm clearly distinguished it from that of the normal colon mucosa. In the human colon mucosa, the activities of ribonucleotide reductase, inosine phosphate dehydrogenase, formylglycinamidine ribonucleotide synthetase, guanosine phosphate synthetase, and amidophosphoribosyltransferase were 0.042, 5.2, 5.6, 8.2 and 36.0 nmol/h/mg protein, respectively, and in the colon carcinomas the activities increased to 755, 575, 295, 280, and 294% of the normal values. The activities of the salvage enzymes, adenine and hypoxanthine-guanine phosphoribosyltransferases, were 310, 249, and 602 nmol/h/mg protein, respectively, whereas in the tumors, only the activity of adenine phosphoribosyltransferase was increased (2-fold). The markedly higher absolute enzymic capacity for salvage in the tumors accounts, in part at least, for the lack of chemotherapeutic success of inhibitors of enzymes of de novo synthesis that have been used in the clinical treatment of colorectal carcinomas. Combinations of inhibitors of de novo biosynthesis and blockers of the salvage enzymes or of salvage transport (e.g., dipyridamole) should improve the chemotherapy of colon neoplasms. Since in the colon carcinoma the activities of glutamine-utilizing enzymes (guanosine phosphate and formylglycinamidine ribonucleotide synthetase and amidophosphoribosyltransferase) were markedly increased, and the glutamine concentration was decreased (50%), treatment with an antiglutamine agent (e.g., acivicin) should be of relevance. Since the activity of ribonucleotide reductase, the rate-limiting enzyme of nucleic acid biosynthesis, was markedly increased in the colon neoplasms, combination chemotherapy might include drugs against this enzyme.
本研究的目的是阐明人类原发性结直肠癌的嘌呤酶程序。人类结肠肿瘤酶学的显著改变使其与正常结肠黏膜明显区分开来。在人类结肠黏膜中，核糖核苷酸还原酶、肌苷磷酸脱氢酶、甲酰甘氨脒核糖核苷酸合成酶、鸟苷磷酸合成酶和氨甲酰磷酸核糖基转移酶的活性分别为0.042、5.2、5.6、8.2和36.0 nmol/h/mg蛋白，而在结肠癌中，这些活性分别增加至正常值的755%、575%、295%、280%和294%。补救酶腺嘌呤和次黄嘌呤 - 鸟嘌呤磷酸核糖基转移酶的活性分别为310、249和602 nmol/h/mg蛋白，而在肿瘤中，只有腺嘌呤磷酸核糖基转移酶的活性增加（2倍）。肿瘤中补救的绝对酶活性明显更高，这至少部分解释了在结直肠癌临床治疗中使用的从头合成酶抑制剂化疗失败的原因。从头生物合成抑制剂与补救酶或补救转运阻滞剂（如双嘧达莫）联合应用应能改善结肠癌的化疗效果。由于在结肠癌中利用谷氨酰胺的酶（鸟苷磷酸和甲酰甘氨脒核糖核苷酸合成酶以及氨甲酰磷酸核糖基转移酶）的活性明显增加，而谷氨酰胺浓度降低（50%），使用抗谷氨酰胺剂（如阿西维辛）治疗可能具有相关性。由于核酸生物合成的限速酶核糖核苷酸还原酶的活性在结肠肿瘤中明显增加，联合化疗可能包括针对该酶的药物。
