Nonclassical Platinum Antitumor Agents: Perspectives for Design and Development of New Drugs Complementary to Cisplatin

Abstract

Studies over the last few years have shown that the range of platinum complexes with useful cytotoxicity and antitumor activity is not strictly limited to structural analogs of cisplatin. In general, we can expect that cells will process structurally different species in different manners. The metabolic chemistry and DNA binding will be altered in in comparison to the cis-[PtX2 (amine)2] class. This point is of particular importance because any altered pattern of antitumor activity of structural analogs of cisplatin is likely to be due to unpredictable pharmacokinetic, rather than truly mechanistic, factors. The fact that discrete cisplatin-DNA adducts vary in their biological activity further supports the hypothesis that complexes structurally dissimilar to cisplatin may produce biological activity complementary to the parent drugs. The mechanism of action of nonclassical complexes is different from that of cisplatin and its analogs. Their pattern of antitumor activity is also altered with respect to cisplatin--thus, not all platinum-containing drugs need necessarily be similar in their clinical profile to cisplatin. Note that both the dinuclear bis(platinum) complexes and the trans complexes give their own distinct patterns of tumor specificity--different from cisplatin and each other (see Tables 1 and 3). New cytotoxic mechanisms for platinum complexes may also be placed in context with cisplatin resistance. Modes of overcoming cisplatin resistance may reside at the various levels of uptake, interaction with "detoxifying" intracellular thiols, and DNA repair. Likewise complexes with novel mechanisms of action may circumvent resistance by more than one unique route. Indeed, the three major routes to resistance are all affected to varying degrees by the complexes outlined above. From the discovery of cisplatin, the development of analogs has essentially been an empirical exercise. Because of their similar mechanism of action, much comparison has been made between platinum complexes and the classic alkylating agents. Yet the alkylating agents represent a good example where a number of structurally distinct drugs with different anticancer activities are clinically available. This desirable feature may be achieved for platinum complexes by emphasis on complexes structurally dissimilar to the presently used agents. The dinuclear bis(platinum) complexes and mononuclear complexes in the trans geometry are of special interest. Comparison of common features and differences between different classes may point to guidelines for the rational design of complexes with a different spectrum of clinical antitumor activity to cisplatin and activity against cisplatin-resistant tumors.