DNA加合物的化疗药物。

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菲利普斯·罗莉PD, DH

DNA加合物的化疗药物。

Mutat研究》1996年8月17日;355 (1 - 2):13-40。0027 - 5107 . doi: 10.1016 / (96) 00020 - 6。

PubMed ID
8781575 (在PubMed
]
文摘

早期工作的指导原则是假设抗癌烷基化交联高分子药物通过他们的行动能力必不可少的细胞分裂。不久之后,DNA被指定为基本目标,并支持假设来自证据表明典型的代理,芥子气,可能链接鸟嘌呤碱基的DNA通过N-7原子。定量烷基化的DNA之间的相关性及其失活作为模板,以噬菌体为一个简单的测试对象,显示平均致死剂量接近一个基因组中交联。这一结论适用于芥子气或最近介绍了铂药物。尽管国际米兰和intra-strand交叉连接是有效的,它被认为在细胞inter-strand交联,通过阻止细胞分裂所需的链的分离,更难以修复,更有效地构成了致命的损伤。repair-deficient细菌,还出现了一个基因组中交联是致命的,但精通细菌可以去除约20通过切除修复交叉连接。Mono-7-alkylguanines还没有废去,显然是惰性。因此,只有几个百分点的烷基化产品最有效的病变。平行研究哺乳动物细胞培养了相当不同的画面,在均值甚至致命剂量的高度敏感细胞株在20或更多的交叉连接基因组,与细菌的耐药菌株。大多数细胞能够承受数百每个基因组的交叉连接,虽然加合物被移除,有不完整的交叉连接。 Some, but not all, sensitive cell lines were deficient in excision repair. Methods were devised for measuring the extents of alkylation of DNA in cells of patients treated with chemotherapeutic drugs; these are mainly immunoassays, and were applied generally to peripheral blood leukocytes, although some tumours were studied. Extents of alkylation of leukocyte DNA were generally of the same order as, or rather less than the mean lethal doses of cultured cells of the 'normal' type, but in some reports for cisplatin-treated patients, very wide variability between individuals was found. A positive correlation between adduct levels, and particularly a very minor adduct recognised specifically by one antibody, and favourable therapeutic outcome was discerned, and suggested to have a pharmacogenetic basis. In several instances, extents of alkylation of tumours were significantly higher than the average for leukocytes; for ovarian and a testicular tumour for cisplatin, and for a plasma cell tumour for melphalan. Nevertheless, these favourable examples would not constitute more than three or four mean lethal doses in the tumour cells, assuming that they had the same sensitivity as 'normal' cell lines: the therapeutic effect would of course be much more favourable if the tumour cells resembled 'sensitive' cell lines. This lack of a favourable difference between extents of alkylation in DNA of patients and the mean lethal dose for normal cells was particularly obvious with the methylating drugs dacarbazine and procarbazine. These considerations stress the need for higher extents of alkylation to be achieved in target tumour DNA for successful chemotherapy. One approach is to give a higher overall dose, and to 'rescue' the bone marrow (known from the earliest report on mustard gas to be the most susceptible tissue) by autologous transplantation. The second, which has yet to reach the clinic, is to convert unreactive prodrugs through enzymic activation into alkylating agents specifically in tumours (see Bagshawe, 1994).

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