The Role of Platinum Complexes in Combined Modality Therapy

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Platinum complexes are one of the most important classes of antitumor agents to enter the clinic in the last 30 yr. Cisplatin (cis-diamminedichloroplatinum II), the first of a group of antitumor platinum complexes, was shown by Rosenberg et al. (1) to possess antibiotic activity and in subsequent studies (2) to have antitumor activity in murine tumor models. In 1972 the National Cancer Institute introduced cisplatin into clinical trials. Cisplatin is a water-soluble inorganic square planar coordination complex containing a central platinum atom surrounded by two chlorine atoms and two ammonia moieties (Fig. 1). Platinum complexes are characterized by slow rates of ligand substitution reactions compared with other metal complexes (3–5). Because of the slow reactions involved in platinum drugs binding to DNA, other intracellular nucleophiles such as glutathione may compete with DNA for reaction (6). Platinum complexes may also bind to metallothioneins, cytosolic proteins of molecular weight 6000–7000 that contain 20 cysteine residues (7). The primary mechanism of inhibition of tumor growth by cisplatin appears to be inhibition of DNA synthesis (8,9). The cis configuration of the chloride leaving groups of cisplatin favors the formation of intrastrand crosslinks in DNA (10–14). Recently, the crystal structure of a double-stranded DNA decamer containing a single interstrand crosslink of cisplatin formed between opposite guanine residues in the 5′-GC sequence was solved (15). In another study using short oligodeoxyribonucleotides duplexes (10 and 20 base pairs) containing a central sequence AGCGA/TCGCT, the interstrand crosslink formed by cisplatin between guanine residues in the opposite strands in the 5′-GC sequence was labile at 37°C and rearranged into an intrastrand crosslink (16). Thus, the frequency of specific cisplatin adducts could be locally and transiently altered in DNA in the cell nucleus during some phase (or phases) of the cell cycle and could be different from those in DNA modified in cell-free media (17). DNA interstrand crosslinks of cisplatin inhibit transcription elongation by both prokaryotic and eukaryotic RNA polymerases (18) and thus may be more lethal than the more frequent intrastrand crosslinks (17).