Chemistry and molecular biology of anticancer platinum drugs

Abstract

The anticancer platinum drug cis-diamminedichloroplatinum(II) ( cis-DPP) binds avidly to DNA both in vitro and in vivo. The mechanism by which cis-DDP kills tumor cells is thought to involve DNAPt interactions [1], but further experimental work to establish this point would be valuable. Accordingly, in joint studies with M. Poirier and her group at the National Cancer Institute, we have developed an antibody to cis-DDP-DNA adducts formed in vitro which reacts specifically with cis-DDPDNA adducts extracted from leukemia cells of mice treated with the platinum drug [2]. Though these antibody studies and other work using nucleases, especially restriction enzymes and exonuclease III, to probe the nature of the cis-DDPDNA binding stereochemistry we find substantial evidence to support the hypothesis that the cis-(NH 3 2Pt 2+ unit forms an intrastrand crosslink between two adjacent or nearby guanine bases on DNA [3]. The stereochemistry of this adduct has been deduced by NMR studies of a model complex formed between the self-complementary hexanucleoside pentaphosphate d(ApGpGpCpCpT) and cis-DDP. In this complex the two adjacent guanine bases are coordinated to the cis-diammineplatinum(II) moiety through their N-7 nitrogen atoms [4]. When cis-DPP is administered in chemotherapy it is invariably used in combination with other anticancer drugs. How do these drugs affect the chemistry of cis-DDP within the cell? Moreover, agents within the cell such as glutathione are known to form complexes with cis-DDP. Will these intracellular reactions affect the DNA- cis-DDP interaction? With these questions in mind we have studied the binding of cis-DDP to DNA plasmids and restriction fragments. Our results demonstrate that the minor groove intercalating drug ethidium bromide switches the nuclease sensitive binding sites of cis-DDP [5] and that glutathione also alters the DNA binding properties of the antitumor drug. Finally, an investigation has been conducted using 195Pt NMR spectroscopy which demonstrates the kinetic mobility of diammineplatinum(II) adducts of the nucleobase analog α-pyridone [6]. In particular, the head-to-head isomer of [(en)Pt(C 5H 4NO)] 2+ 2 ▪ rearranges thermally to the head-to-tail isomer by a process that is reversible, intramolecular, and dissociatively activated. The possible relevance of this isomerization reaction to cis-DPPDNA adducts will be discussed.