EFFECT OF THE AMINE NONLEAVING GROUP ON THE STRUCTURE AND STABILITY OF DNA COMPLEXES WITH CIS-[PT(R-NH2)2(NO3)2]

被引:37
作者
BUTOUR, JL
ALVINERIE, P
SOUCHARD, JP
COLSON, P
HOUSSIER, C
JOHNSON, NP
机构
[1] CNRS,PHARMACOL & TOXICOL FONDAMENTALES LAB,205 ROUTE NARBONNE,F-31077 TOULOUSE,FRANCE
[2] STATE UNIV LIEGE,CHIM MACROMOLEC & CHIM PHYS LAB,B-4000 LIEGE,BELGIUM
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 1991年 / 202卷 / 03期
关键词
D O I
10.1111/j.1432-1033.1991.tb16458.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The antitumor compound cis-[Pt(NH3)2Cl2] (cisplatin), conserves two ammine ligands during the reaction with its cellular target DNA. Modifications of these non-leaving groups change the antineoplastic properties of this compound and its genotoxic effects. It is therefore of interest to determine the influence of non-leaving groups on the structure and stability of DNA in vitro. We have investigated platinum-DNA adducts formed by cis-[Pt(R-NH2)2(NO3)2] (where R-NH2 = NH3, methylamine, cyclobutylamine, cyclopentylamine and cyclohexylamine) as a function of DNA binding. All compounds quantitatively reacted with DNA in less than 1 h at 37-degrees-C. They formed bifunctional adducts with adjacent nucleotides judging from the displacement of the intercalating molecule ethidium bromide, ultraviolet absorption spectroscopy and circular dichroism. Substitution of a H on the NH3 ligand by alkyl groups dramatically destabilized the platinum-DNA complex. Thermal stability decreased progressively with an increasing number of carbon atoms, DELTA-t(m) = -4.4-degrees-C for 3 cyclohexylamine-platinum-DNA adducts/1000 nucleotides, conditions where cisplatin had no effect. DNA adducts with cyclobutylamine and cyclohexylamine ligands inhibited the hydrolysis of platinum-DNA complexes by S1 nuclease. K(m) for the digestion of DNA containing these lesions was 2.3 times greater than for cisplatin, indicating steric inhibition of enzyme-substrate complex formation. These results show that the non-leaving groups of substituted cis-Pt(II) compounds may destabilize DNA and interfere with protein-DNA interactions. These perturbations may have consequences for the genotoxic and antitumor activities of platinum compounds.
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页码:975 / 980
页数:6
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