Role of ribonucleotide reductase in expression in the neoplastic program.
Role of ribonucleotide reductase in expression in the neoplastic program.
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DOI：
10.1016/0024-3205(81)90746-3
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发表时间：
1981-03
期刊：
影响因子：
6.1
通讯作者：
Eiji Takeda;George Weber
中科院分区：
文献类型：
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作者：
Eiji Takeda;George Weber
证据是紧密联系的核糖核苷酸还原酶活性与正常和肿瘤增殖。本文报道了一种灵敏、重复性好的测定大鼠正常肝、各种组织、不同生长速度的肝癌、肾癌、肉瘤及肝癌3924 A组织培养细胞CDP还原酶活性的方法。在标准测定中，获得线性动力学，大鼠肝脏的还原酶活性为23±3 pmol CDP代谢/hr/mg蛋白质。当将在平台期积累的肝癌3924 A组织培养细胞重新铺板，使其在96小时期间经历滞后期和对数期并再次进入平台期时，核糖核苷酸还原酶活性在细胞铺板后6小时升高，在前48小时期间该活性维持在高水平，这种升高早于嘧啶从头合成途径和补救途径的其他6种酶（胸苷激酶、CTP合成酶、乳清酸核苷-5 ′-磷酸脱羧酶、乳清酸磷酸核糖基转移酶、尿苷磷酸核糖基转移酶和尿苷-胞苷激酶）。还原酶活性的升高与肝癌细胞胞苷和脱氧胞苷掺入量的增加同步。还原酶活性显着升高，在肾肿瘤（31倍）和肉瘤（60倍）相比，肾皮质和肌肉，分别。在14行可移植性实体肝癌，还原酶活性从6.2增加到326倍的正常大鼠肝脏。还原酶活性的升高与肝癌的生长速度呈正相关; CDP还原酶的行为与转化和进展有关。还原酶活性在分化和再生肝脏中也很高;因此，它也与正常增殖有关。然而，活性的升高在快速生长的实体肝癌3924 A（97倍）中比具有相同复制率的正常组织（例如再生（56倍）或分化（46倍）肝）中更显著。在活跃细胞更新的器官（胸腺、骨髓、脾和肠）中还原酶活性也很高。由于在实体性肝癌中，还原酶的底物核糖核苷二磷酸的水平通常不变，因此观察到的脱氧核苷三磷酸浓度的显著升高可能主要归因于CDP还原酶活性的早期和显著升高。
Evidence is presented for the tight linkage of ribonucleotide reductase activity with normal and neoplastic proliferation. A sensitive and reproducible assay was worked out to measure CDP reductase activity in rat in normal liver and various tissues, hepatomas of different growth rates, kidney tumors and sarcoma and tissue culture cells of hepatoma 3924A. In the standard assay, linear kinetics were obtained and the reductase activity of the rat liver was 23±3 pmol CDP metabolized per hr/mg protein. When hepatoma 3924A tissue culture cells that had accumulated in plateau phase were replated, allowed to go through lag and log phases and again into the plateau phase during a 96-hr period, ribonucleotide reductase activity rose at 6 hr after cells were plated, the activity was maintained at high levels during the first 48-hr period, and returned to the resting level at 72 and 96 hr. This rise was earlier than that of 6 other enzymes of pyrimidine de novo and salvage pathways (thymidine kinase, CTP synthetase, orotidine-5′-phosphate decarboxylase, orotate phosphoribosyltransferase, uridine phosphoribosyltransferase, and uridine-cytidine kinase). The rise in reductase activity was synchronous with the increase in incorporation of cytidine and deoxycytidine in the hepatoma cells. The reductase activity was markedly elevated in kidney tumors (31-fold) and in sarcoma (60-fold) as compared to the kidney cortex and muscle, respectively. In 14 lines of transplantable solid hepatomas, reductase activity was increased from 6.2-to 326-fold of that of normal rat liver. The rise in reductase activity positively correlated with the growth rate of the hepatomas; the behavior of CDP reductase was both transformation-and progression-linked. Reductase activity was also high in differentiating and regenerating liver; thus, it also was linked with normal proliferation. However, the elevation in activity was more marked in the rapidly-growing solid hepatoma 3924A (97-fold) than in normal tissues with the same replicative rate, such as regenerating (56-fold) or differentiating (46-fold) liver. Reductase activity was also high in organs of active cell renewal (thymus, bone marrow, spleen and intestine). Since in the solid hepatomas the levels of the substrate for the reductase, the ribonucleoside diphosphates, were generally unaltered, the marked elevation observed in the concentration of deoxynucleoside triphosphates may be attributed primarily to the early and marked rise in CDP reductase activity.