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Modulation of cancer pathways by inhibitors of guanylate metabolism

机译:鸟苷酸代谢抑制剂对癌症途径的调节

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There is compelling evidence that misregulation of key signaling pathways by mutated genes that are causally implicated in oncogenesis is a feature of many common cancers. The damage of these cancer genes potentiates cell survival, proliferation and key elements in tumor progression (Bishop, 1987, 1991; Hanahan and Weinberg, 2000). Complexity of malignant phenotype includes enzymic and metabolic imbalance of cancer cells (Weber, 1983). A "comprehensive biochemical strategy of cancer cells" was revealed by Weber (1983), thus introducing a rational approach for the design of enzyme and metabolism pattern-directed anticancer chemotherapy. His major proposals include that (1) the biochemical strategy of the genome in neoplasia can be identified by elucidating the pattern of reprogrammed gene expression, (2) the activity of key enzymes and metabolic pathways (and concentrations of strategic metabolites) are stringently linked with the neoplastic phenotype. According to this concept the increased capacity ofthe guanylate synthetic pathway provides an advantage for growth and progression of tumors. IMP dehydrogenase (IMP DH) (EC 1.1.1.205) is the rate-limiting enzyme of GTP biosynthesis and a key component in the biochemical program of cancer cells; therefore it was suggested as a sensitive target for cancer chemotherapy (Weber, 1983).
机译:有令人信服的证据表明,与致癌作用有因果关系的突变基因对关键信号通路的失调是许多常见癌症的特征。这些癌症基因的损伤增强了细胞存活,增殖和肿瘤进展中的关键要素(Bishop,1987,1991; Hanahan and Weinberg,2000)。恶性表型的复杂性包括癌细胞的酶和代谢失衡(Weber,1983)。 Weber(1983)揭示了“癌细胞的综合生化策略”,从而为设计酶和代谢模式指导的抗癌化学疗法引入了合理的方法。他的主要建议包括:(1)可以通过阐明重新编程的基因表达模式来确定瘤形成中的基因组的生化策略;(2)关键酶的活性和代谢途径(以及战略代谢物的浓度)与肿瘤表型。根据该概念,鸟苷酸合成途径的能力增加为肿瘤的生长和发展提供了优势。 IMP脱氢酶(IMP DH)(EC 1.1.1.205)是GTP生物合成的限速酶,是癌细胞生化程序中的关键成分。因此建议将其作为癌症化疗的敏感靶标(Weber,1983)。

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