Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer.
Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer.
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DOI：
10.1021/cr900028p
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发表时间：
2009-07
期刊：
影响因子：
62.1
通讯作者：
Parker, William B.
中科院分区：
文献类型：
--
作者：
Parker, William B.
抑制细胞复制是癌细胞的一个特征，过去已经有效地利用它来开发抗癌药物。目前用于杀死癌细胞的大多数药物都会抑制DNA的合成，或者以这样或那样的方式干扰其功能。一个细胞要分裂成两个细胞，它必须复制包括其基因组在内的所有成分，而且与其他主要大分子(蛋白质、RNA、脂类等)的合成不同，DNA的合成在静止的细胞中不会发生很大程度的合成。由于成年生物体中的大多数细胞都处于静止状态，并不处于复制基因组的过程中，因此靶向DNA复制提供了一定程度的选择性。当然，某些组织(骨髓、胃肠道、毛囊等)处于复制状态，所有细胞都必须持续修复它们的DNA。因此，抑制正常组织中的DNA复制会导致相当大的毒性，限制了患者可以耐受的药物数量。尽管存在这个问题，但已经开发出了非常有效的抗癌药物，可以提高患者的存活率，在某些情况下，还可以治愈患者的疾病。人类细胞具有挽救嘌呤和嘧啶的能力，用于合成用于DNA合成的脱氧核苷酸，这些核苷酸前体的类似物已被证明是一类重要的抗癌药物。被FDA批准用于治疗癌症的嘌呤和嘧啶类抗代谢药物共有14种(表1)，占所有用于治疗癌症的药物的近20%。FDA批准的第一批用于治疗癌症的化合物中，有一些就属于这类化合物。6-巯基嘌呤于1953年被批准用于儿童白血病的治疗，在那里它是治愈的，并且仍然是这种疾病的标准治疗方法。自1991年以来，FDA已经批准了9种核苷类似物用于治疗各种恶性肿瘤。自2004年以来，这些新的代理商中有四个获得了批准，而且有许多
Inhibition of cellular replication is one characteristic of cancer cells that has been effectively exploited in the past for the development of anticancer agents. Most of the drugs currently used to kill cancer cells inhibit the synthesis of DNA or interfere with its function in one manner or another. For a cell to divide into two cells, it must replicate all components including its genome, and unlike the synthesis of other major macromolecules (protein, RNA, lipid, etc.), the synthesis of DNA does not occur to a great degree in quiescent cells. Since most cells in an adult organism are quiescent and are not in the process of duplicating their genome, targeting DNA replication affords some level of selectivity. Of course, certain tissues (bone marrow, gastrointestinal, hair follicles, etc.) are in a replicative state, and all cells must continually repair their DNA. Therefore, inhibition of DNA replication in normal tissues results in considerable toxicity that limits the amount of drug that can be tolerated by the patient. In spite of this problem, very effective anticancer drugs have been developed that increase survival and, in some cases, cure the patient of his or her disease.Human cells have the capacity to salvage purines and pyrimidines for the synthesis of deoxyribonucleotides that are used for DNA synthesis, and analogues of these nucleotide precursors have proven to be an important class of anticancer agents. There are a total of 14 purine and pyrimidine antimetabolites that are approved by the FDA for the treatment of cancer (Table 1), which account for nearly 20% of all drugs that are used to treat cancer. Some of the first compounds approved by the FDA for the treatment of cancer were in this class of compounds. 6-Mercaptopurine was approved in 1953 for the treatment of childhood leukemia, where it is curative and is still the standard of treatment for this disease. Since 1991, nine nucleoside analogues have been approved by the FDA for the treatment of various malignancies. Four of these new agents were approved since 2004, and there are numerous
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影响因子：
56.9
作者：
ELION, GB
通讯作者：
ELION, GB
影响因子：
4.8
作者：
Chou, KM;Kukhanova, M;Cheng, YC
通讯作者：
Cheng, YC
DOI：
10.1073/pnas.89.7.2970
发表时间：
1992-04-01
影响因子：
11.1
作者：
CARSON, DA;WASSON, DB;COTTAM, HB
通讯作者：
COTTAM, HB
影响因子：
3.6
作者：
Clarke, Marilyn L.;Damaraju, Vijaya L.;Cass, Carol E.
通讯作者：
Cass, Carol E.
DOI：
10.1016/s1521-6926(02)00089-0
发表时间：
2003-03-01
影响因子：
2.1
作者：
Goodman, GR;Beutler, E;Saven, A
通讯作者：
Saven, A