DNA INTERACTIONS OF ANTITUMOR PLATINUM(IV) COMPLEXES

被引:62
作者
NOVAKOVA, O [1 ]
VRANA, O [1 ]
KISELEVA, VI [1 ]
BRABEC, V [1 ]
机构
[1] ACAD SCI CZECH REPUBL,INST BIOPHYS,CS-61265 BRNO,CZECH REPUBLIC
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 1995年 / 228卷 / 03期
关键词
DNA; PLATINUM(IV); ANTITUMOR ACTIVITY; PLATINUM DRUGS;
D O I
10.1111/j.1432-1033.1995.tb20301.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
Modifications of natural DNA and synthetic double-stranded oligodeoxyribonucleotides by cis-diamminedichloro-trans-dihydroxyplatinum(Iv) (oxoplatin) were studied by means of ELISA, Maxam-Gilbert footprinting techniques, HPLC of enzymically digested DNA, and transcription assay. It was found that oxoplatin can bind DNA directly without addition of a reducing agent. In addition, the antibodies elicited against DNA modified by cisplatin were not competitively inhibited by DNA modified by oxoplatin. However, DNA containing the adducts of oxoplatin became a strong inhibitor of these antibodies, if it was subsequently treated with ascorbic acid, which is a reducing agent. These results were interpreted to mean that oxoplatin can form DNA adducts containing the platinum moiety in the quadrivalent state. The direct irreversible binding of the platinum(IV) drug is, however, slow as compared to the reaction of its platinum(II) counterpart. It was also found that oxoplatin preferentially binds to guanine residues and can form DNA intrastrand and interstrand cross-links containing platinum(IV). The DNA adducts containing platinum(IV) can inhibit in vitro transcription by a prokaryotic DNA-dependent RNA polymerase. We find that the platinum(IV) complex binds to DNA at similar sites as its platinum(lI) counterpart. On the other hand, the DNA adducts containing the platinum(II) or platinum(IV) analogues differ in the number of ligands and the formal charge on their platinum center. We suggest that these differences could be responsible for distinct conformational features and stability of DNA modified by platinum(II) or platinum(TV) complexes.
引用
收藏
页码:616 / 624
页数:9
相关论文
共 60 条
[1]   LABILITY OF MONOFUNCTIONAL CISPLATINUM ADDUCTS - ROLE OF DNA DOUBLE HELIX [J].
ANIN, MF ;
GAUCHERON, F ;
LENG, M .
NUCLEIC ACIDS RESEARCH, 1992, 20 (18) :4825-4830
[2]   PT-195 NMR KINETIC AND MECHANISTIC STUDIES OF CIS-DIAMMINEDICHLOROPLATINUM AND TRANS-DIAMMINEDICHLOROPLATINUM(II) BINDING TO DNA [J].
BANCROFT, DP ;
LEPRE, CA ;
LIPPARD, SJ .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1990, 112 (19) :6860-6871
[3]  
BARNARD CFJ, 1986, CHEM BRIT, V22, P1001
[4]  
Begg A C, 1988, NCI Monogr, P133
[5]  
BELLUCO U, 1974, ORGANOMETALLIC COORD, P166
[6]  
BLATTER EE, 1984, BIOCHEMISTRY-US, V23, P4817, DOI 10.1021/bi00316a001
[7]   DNA INTERSTRAND CROSS-LINKS OF TRANS-DIAMMINEDICHLOROPLATINUM(II) ARE PREFERENTIALLY FORMED BETWEEN GUANINE AND COMPLEMENTARY CYTOSINE RESIDUES [J].
BRABEC, V ;
LENG, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (11) :5345-5349
[8]  
BRABEC V, 1983, COLLECT CZECH CHEM C, V48, P2903
[9]   DNA CONFORMATIONAL CHANGE PRODUCED BY THE SITE-SPECIFIC INTERSTRAND CROSS-LINK OF TRANS-DIAMMINEDICHLOROPLATINUM(II) [J].
BRABEC, V ;
SIP, M ;
LENG, M .
BIOCHEMISTRY, 1993, 32 (43) :11676-11681
[10]  
BRABEC V, 1986, STUD BIOPHYS, V114, P199