Platinum Metals Rev., 1999, 43, (2), 61
Anticancer Properties of Platinum (IV) Complexes
Since Barnett Rosenberg published the first work on the antitumour activity of platinum compounds 30 years ago, platinum-based drugs have made a major contribution to cancer therapy (1). Cisplatin, the first platinum anticancer drug, and the later platinum drugs developed, are widely used to treat lung, ovarian, testicular, head and neck, and bladder cancers and many other tumours (2). It is generally established that DNA is the primary target for platinum anticancer drugs and much work has gone into examining the mechanisms of activity taking place.
Now, scientists in the Netherlands, have investigated the activity of Pt(IV) compounds as antitumour agents to discover whether such compounds are real drugs or, as is widely believed, act as prodrugs, that is they are reduced to Pt(II) before reaching their DNA target (3). A prodrug is a compound converted within the body to its active form. It is used when the active drug is too toxic for direct administration, or is poorly absorbed, or would be broken down before finding its target.
Pt(IV) is kinetically more inert than Pt(II), which means Pt(IV) drugs are more stable to acidic media, so may survive the conditions present in the stomach, and thus can be administered orally. Pt(IV) drugs are of particular interest since they may be toxic to tumours which are normally resistant to cisplatin. Pt(IV) amine complexes, with the chelating ligand trans -R, R-diaminocyclohexane and other co-ordinating anions, were reacted with DNA model bases, such as 9-methylxanthine and 9-methylhypoxanthine. The nature of the anions, and of the DNA model base, was found to determine the in vitro reactivity of the Pt(IV) compounds. Identical Pt-DNA adducts were detected from reaction with both Pt(IV) and Pt(II), suggesting that the mechanism of inhibition of DNA replication is the same for Pt(IV) and Pt(II). Reaction occurred in all cases, and Pt(IV)-DNA intermediates were found, so reduction to Pt(II) is not a requirement prior to reaction with DNA. They speculate that Pt(IV) may enter the cell by a different mechanism to Pt(II) and so the possibility remains that some Pt(IV) compounds do not act as prodrugs.
- 1B. Rosenberg,, L. VanCamp,, J. E. Trosko and V. H. Mansour, Nature, 1969, 222, 385
- 2K. R. Harrap, Platinum Metals Rev ., 1984, 28, ( 1 ), 14 ; C. F. J. Barnard, ibid ., 1989, 33, ( 4 ), 162
- 3E. G. Talman,, Y. Kidani,, L. Mohrmann and J. Reedijk, Inorg. Chim. Acta, 1998, 283, ( 1 ), 251