DNA interstrand cross-links induced by the cyclopropylpyrroloindole antitumor agent bizelesin are reversible upon exposure to alkali.
DNA interstrand cross-links induced by the cyclopropylpyrroloindole antitumor agent bizelesin are reversible upon exposure to alkali.
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由环丙基吡咯并吲哚抗肿瘤剂比泽来辛诱导的 DNA 链间交联在暴露于碱后是可逆的。
DOI：
10.1021/bi00086a015
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发表时间：
1993
期刊：
影响因子：
2.9
通讯作者：
Gibson,NW
中科院分区：
文献类型：
--
作者：
Lee,CS;Gibson,NW
摘要：比泽来新是一种环丙基吡咯并吲哚（CPI）抗肿瘤药物，已被证明可在富含A/T的区域内烷基化和交联DNA。先前的研究表明，CPI阿多来新与DNA的共价反应是可逆的[Warpehoski，MA，哈珀，DE，Mitchell，M.一、&门罗，T. J.（1992）Biochemistry 31，2502-2508]。也就是说，单官能加合物可以从DNA中丢失，从而恢复DNA的保真度。在这项研究中，我们证明了由bizelesin在腺嘌呤N3位置诱导的共价DNA加合物经历了两个随后的竞争反应：一个通过脱嘌呤引起DNA链切割，另一个通过DNA加合物的损失进行（加合物逆转与DNA完整性的恢复）。我们的结果是通过研究合成的DNA寡核苷酸的化学稳定性，其中包含一个独特的DNA单官能加合物或DNA链间交联。加合物逆转的定量进行的基础上，药物修饰的DNA，暴露于热，然后热哌啶处理，是耐链裂解的烷基化位点。发现加合物反转速率随温度的升高而增加，并发现在70-80 ℃时最大。加合物反转速率也随pH值和离子强度的增加而增加。与此相反，脱嘌呤和随后的DNA链裂解的速度下降的pH值和离子强度的增加。加合物逆转在含有链间交联的DNA中是有利的，而快速脱嘌呤优先发生在单官能烷基化的DNA中。CC-1065（图1）是一种非常有效的抗肿瘤抗生素，能够以序列选择性方式烷基化腺嘌呤N3位置（Hurley等人，1984，1988，1990; Reynolds等人，1985; Boger等人，1988年、1990年、1991年a-c）。CC-1065的合成双功能类似物比泽来新含有两个与刚性双（吲哚羧酸）接头连接的DNA反应性环丙基吡咯并吲哚（CPI）1亚基（Mitchell等人，
Revised Manuscript Received June 4, 1993• abstract: Bizelesin, a cyclopropylpyrroloindole (CPI) antitumor agent, has been shown to alkylate and cross-link DNA within A/T-rich tracts. Previous studies have shown that covalent reaction of the CPI adozelesin with DNA was reversible [Warpehoski, MA, Harper, DE, Mitchell, M. A., & Monroe, T. J.(1992) Biochemistry 31, 2502-2508]. That is, the monofunctional adduct could be lost from DNA, thus restoring the fidelity of DNA. In this study, we demonstrate that covalent DNA adducts induced by bizelesin at the adenine N3 positionundergo two subsequent competing reactions: one which causes DNA strand cleavage, via depurination, and one which proceeds through loss of the DNA adduct (adduct reversal with restoration of DN A integrity). Our results were obtained by studying the chemical stability of synthetic DNA oligonucleotides which contained either a distinct DNA monofunctional adduct or DNA interstrand cross-links. Quantification of adduct reversal was performed on the basis that drug-modified DNA, upon exposure to heat followed by hotpiperidine treatment, was resistant to strand cleavage at the site of alkylation. The rate of adduct reversal was found to increase with increasing temperature and was found to be maximum at 70-80 C. Therate of adduct reversal was also found to increase with increasing pH and ionic strength. In contrast, the rate of depurination and subsequent DNA strand cleavage decreased as pH and ionic strength were increased. Adduct reversal was favored in DNA containing interstrand cross-links, whereas rapid depurination occurred preferentially within monofunctionally alkylated DNA.CC-1065 (Figure 1) is a very potent antitumor antibiotic capable of alkylatingthe adenine N3 position in a sequenceselective manner(Hurley et al., 1984, 1988, 1990; Reynolds et al., 1985; Boger et al., 1988, 1990, 1991a-c). Bizelesin, a synthetic bifunctional analog of CC-1065, contains two DNA-reactive cyclopropylpyrroloindole (CPI) 1 subunits connected with a rigid bis (indolecarboxylic acid) linker (Mitchell et al.,
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DOI：
10.1126/science.6222474
发表时间：
1983
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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DOI：
10.1084/jem.135.6.1316
发表时间：
1972-06-01
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Manning DD;Jutila JW
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Jutila JW
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影响因子：
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作者：
G. Woloschak
通讯作者：
G. Woloschak
DOI：
10.1084/jem.135.2.277
发表时间：
1972-02-01
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Lawton AR 3rd;Asofsky R;Hylton MB;Cooper MD
通讯作者：
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