The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes.

Charles F. Kettring prize. Fundamental studies with cisplatin

Binding of the antitumor drug cis-diamminedichloroplatinum(II) (Cisplatin) to DNA

Cis-diamminedichloroplatinum (II) (DDP) leads the series of platinum coordination complexes, a new class of cytotoxic agents. The antitumor and toxic effects of this drug are discussed. It has displayed encouraging results in testicular tumors. The drug's therapeutic effectiveness has also been recognized in a variety of other solid tumors, particularly ovarian, bladder, and head and neck malignancies. Gastrointestinal, renal, audiologic, and relatively minor hematologic toxicities may be encountered, but promising methods have been developed to increase the therapeutic index of DDP.

Cis-diamminedichloroplatinum (II): A New Anticancer Drug

Multiplicity of metal ion binding patterns to nucleobases

ONE of the more effective cis-platinum antitumour compounds currently being tested in cancer chemotherapy is cis-Pt(NH3)2Cl2 (ref. 1). Evidence suggests that DNA is the effective site of action of the platinum drug2,3. This study was initiated to determine the effective binding site on DNA. Roberts and Pascoe have noted the similarity of action between cis-Pt (NH3)2Cl2 and the classical antitumour bifunctional alkylating agents which crosslink DNA (ref. 2). Low concentrations of several cis-platinum compounds suppress DNA synthesis in vitro while affecting protein and RNA synthesis to a much lesser extent3. The studies by Horacek and Drobnik employing ultraviolet absorption spectroscopy indicate that the platinum moiety binds to the bases of DNA rather than to the phosphate backbone4. Spectroscopic studies suggest that cis-Pt(NH3)2Cl2 preferentially binds to guanine–cytosine (G–C)-rich DNA5,6. An increase in the buoyant density of T7 DNA and calf thymus DNA has been reported when one of several platinum compounds is present in solution5,7. Here we report that the binding of cis-Pt(NH3)2Cl2 to DNA results in large increases in buoyant density which are proportional to the G–C content of the DNA and to the molar ratio of platinum to DNA-P.

A D Kelman

Papers

Specific binding of antitumour drug cis -Pt(NH 3 ) 2 Cl 2 to DNA rich in guanine and cytosine