Tumor cells, with acquired resistance cisplatin

Tumor cells with acquired resistance to cisplatin (a major clinical problem) are known to over-express metallothionein, a protein of —61 amino acids, of which 20 are cysteines. Metallothionein is involved with the natural metabolism of Zn(II) and Cu(I), and all the Cys sul-furs are involved in forming terminal or bridging bonds to the 7-10 metals that form clusters on the protein. Petering et al. (29) have recently shown that en is rapidly released from [Pt(en)Cl2] on reaction with metallothionein in vitro and that the rate-determining step does not involve aqua or hydroxo intermediates. 

ZD0473 (formerly AMD473, JM473) was developed in order to overcome acquired or intrinsic (de novo) resistance to cisplatin. Based on the steric bnlk of its methyl-substituted pyridine moiety, thiol snbstitntion and drug inactivation is hindered compared with cisplatin. In several in-vitro studies, ZD0473 was active even in cisplatin-refractory tumor cells, whose key mechanism of resistance was based on thiol substitution. In addition, ZD0473 is also active in cisplatin-resistant tumor cells, in which resistance is based on altered drug transport mechanisms or enhanced DNA repair. 

Although the second generation of platinum drugs is less toxic than cisplatin, many appear to be cross-resistant with cisplatin. Requirements which are influencing the search for new generations of active complexes include (1) lower toxicity to normal cells than cisplatin, (2) activity against tumors with acquired cisplatin resistance, (3) activity against a wider spectrum of types of cancer, and (4) oral activity. 

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