Interaction of novel bis(platinum) complexes with DNA

• Published in: Nucleic acids research Vol. 17; no. 23; pp. 9719 - 9733
• Main Authors: Roberts, John D., Van Houten, Bennett, Qu, Yun, Farrell, Nicholas P.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 11.12.1989
• Subjects: Base Sequence; Biological and medical sciences; Cisplatin; Cross-Linking Reagents; DNA; DNA Adducts; DNA Damage; DNA, Bacterial - metabolism; Endodeoxyribonucleases - metabolism; Escherichia coli; Escherichia coli - genetics; Escherichia coli Proteins; Fundamental and applied biological sciences. Psychology; Genes, Bacterial; Interactions. Associations; Intermolecular phenomena; Models, Structural; Molecular biophysics; Molecular Sequence Data; Nucleic Acid Conformation; Plasmids; Substrate Specificity; Antineoplastic agent; Plasmid; Autoradiography; Gel electrophoresis; DNA; Molecular interaction; Crosslink agent; Comparative study
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/17.23.9719

Bis(platinum) complexes [[cis-PtCl2(NH3)]2H2N(CH2)nNH2] are a novel series of potential anticancer agents in which two cis-diamine(platinum) groups are linked by an alkyldiamine of variable length. These complexes are potentially tetrafunctional, a unique feature in comparison with known anticancer agents. Studies of DNA interactions of bis(platinum) complexes in comparison with cisplatin demonstrate significant differences. Investigations of interstrand crosslink formation in which crosslinking of a short DNA fragment is detected by gel electrophoresis under denaturing conditions demonstrate that interstrand crosslinks are 250 fold more frequent among bis(platinum) adducts than among cisplatin-derived adducts under the conditions examined. These investigations indicate that bis(platinum) adducts contain a high frequency of structurally novel interstrand crosslinks formed through binding of the two platinum centers to opposite DNA strands. Unlike cisplatin, bis(platinum) complex binding does not unwind supercoiled DNA. Studies with the E. coli UvrABC nuclease complex demonstrate that both linear and supercoiled DNA containing bis(platinum) adducts are subject to incision by the repair enzyme complex. Initial studies using UvrABC nuclease as a probe to define the base and sequence specificity for bis(platinum) complex binding suggest that the specificity of the bis(platinum)s is similar, but not identical, to that of cisplatin.