THE CHEMISTRY AND BIOLOGY OF PLATINUM COMPLEXES WITH THE 1,2-DIAMINOCYCLOHEXANE CARRIER LIGAND (REVIEW)

Dach-Pt compounds have been intensively studied because of their potential. efficacy against cisplatin-resistant tumors and their reduced nephrotoxicity and myelotoxicity compared to cisplatin and carboplatin. Because the dach carrier ligand can be H-3-labeled, the biotransformations of dach-Pt compounds have been studied in detail. Some of these biotransformation studies have provided new information about the likely cellular biotransformation pathways of Pt complexes in general. For example, biotransformation studies with 1,2-diaminocyclohexanedichloroplatinum(II) [Pt(dach)Cl-2] and 1,2-diaminocyclohexanemalonatoplatinum(II) [Pt(dach)(mal)] have shown that displacement of leaving ligands by HCO3- and PO4= are likely to represent important activation pathways for platinum(II) complexes in vivo and that the intracellular t(1/2) is much more rapid [15' for Pt(dach)Cl-2 and 30' for Pt(dach)(mal)] than predicted by previous in vitro experiments. Biotransformation studies with 1,2-diaminocyclohexanetetrachloroplatinum(IV) (ormaplatin) have suggested that Pt(II)-assisted Pt(IV) ligand exchange reactions can occur in vivo with platinum(IV) complexes. This is important for our understanding of platinum(IV) biotransformations because the specificity of Pt(II)-assisted Pt(IV) ligand exchange reactions is different than that for Pt(II) ligand exchange reactions. Finally, plasma biotransformation studies with ormaplatin in vivo have shown that ultrafilterable, active biotransformation products are cleared from the circulation much more rapidly than the ultrafilterable, inactive biotransformation products. This has lead to the suggestion that pharmacokinetic parameters based on the active biotransformation products are likely to be much more useful than pharmacokinetic parameters based on ultrafilterable platinum for predicting the efficacy and/or toxicity of platinum compound with chloro leaving ligands such as ormaplatin and cisplatin. Since dach-Pt compounds can overcome cisplatin resistance in some cancer cell lines but not in others, it is important to understand the mechanism(s) which determine(s) the carrier ligand specificity of resistance. A great deal has been learned about how dach-Pt compounds interact with DNA. The dach carier ligand constrains the N-Pt-N bond angle and can exist as 3 isomers with a total of 4 different non-planar conformations. These constraints do not appear to affect the rate or sequence specificity of Pt-DNA monoadduct formation, but do appear to alter the rate of monoadduct to diadduct conversions. The dach carrier ligand may also have significant effects on the conformation of DNA in the region of Pt-DNA adducts, although the biological consequences of these effects are not clear. Much less is known about the effects of the dach carrier ligand on the interactions of Pt compounds with proteins. Because Pt compounds primarily interact with nonadjacent amino acids on the surface of proteins, these interactions are not likely to be significantly affected by the conformation of dach-Pt compounds. However, the hydrophobicity of the dach carrier ligand may allow it to react with amino acid side chains in hydrophobic pockets that are inaccessible to cisplatin. At the cellular level, the dach carrier ligand appears to affect Pt accumulation in Pt resistant mouse L1210 cells, but has little effect on either Pt uptake or efflux in Pt-resistant human ovarian and colon carcinoma cell lines. While enhanced repair also appears to contribute to resistance in many eel lines, there is little or no difference in the repair of dach-Pt and cis-diammine-Pt adducts in any of the cell lines tested to date. Current data suggest that replicative bypass makes a significant contribution to platinum resistance and, in many cell lines, is the only process to predict the carrier ligand specificity of resistance. These data suggest that further elucidation of this process should add significantly to our understanding of platinum resistance and the role of platinum complexes with the dach carrier ligand in chemotherapy.