细胞毒性抗癌铂药物的机制:证据表明cis-diamminedichloroplatinum (II)和cis-diammine - (1, 1-cyclobutanedicarboxylato)铂(II)只有在不同动力学与DNA的相互作用。

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诺克斯RJ Friedlos F, Lydall哒,罗伯茨JJ

细胞毒性抗癌铂药物的机制:证据表明cis-diamminedichloroplatinum (II)和cis-diammine - (1, 1-cyclobutanedicarboxylato)铂(II)只有在不同动力学与DNA的相互作用。

癌症研究》1986年4月,46 (4 Pt 2): 1972 - 9。

PubMed ID

3512077 (在PubMed

]

文摘

水合作用的动力学反应顺铂和卡铂及其随后的反应和DNA,在体外和体内,被测量。结果外推到显示预期的这些化合物的细胞毒性细胞获得人类的癌症患者。速率常数的水合作用在37摄氏度的顺铂和卡铂8 X 10(5)和7.2 X 10 (7) s - 1,分别计算半衰期的这些化合物在磷酸盐缓冲剂,pH值7。这种差异在他们的激活被绑定到DNA的利率匹配。通过使用14 c-labeled配体,卡铂是显示绑定单功能的DNA,之后有时间形成双官能的interstrand交叉连接,形成于其中的一些最初单功能的加合物。类似,虽然快,积累使交联顺铂时被绑定到DNA。14 c-cbdca配体卡铂的损失计算发生速率常数为1.3 X 10 (5) s - 1的类似interstrand率形成的交叉连接和速度比与DNA单功能的反应。因此得出结论,CBDCA配体变得更加不稳定离去基一旦monoaquated卡铂。相比之下,两个chloro-ligands顺铂的离开与出口增速。事实上其他双病变程度不尽相同,形成平等一定剂量顺铂或卡铂,显示了解除超螺旋质粒DNA。 The effects of cisplatin and carboplatin on this DNA were the same once bound to the same extent. About a 100-fold larger dose of carboplatin was, as predicted by their rates of aquation, required to produce equivalent binding to plasmid DNA. In vivo, equal binding of the two drugs to DNA of various cell systems resulted in equal cytotoxicity. Again a much larger dose (20- to 40-fold) of carboplatin was required to produce this equal binding. In general a DNA bound platinum level of about 20 nmol/g reduced cell survival by 90%, although certain cell lines were shown to be much more sensitive to DNA bound platinum. Similar binding values, to those above, were obtained in the DNA extracted from cells of human cancer patients treated with cisplatin. It was inferred that the cytotoxic effect of this level of platinum on DNA would be (unless the cells were of a sensitive phenotype) about 90%.(ABSTRACT TRUNCATED AT 400 WORDS)

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药物

卡铂