Trans-diammineplatinum(II): what makes it different from cis-DDP? Coordination chemistry of a neglected relative of cisplatin and its interaction with nucleic acids.

The question raised, i.e., "trans-diammineplatinum(II)--what makes it different from its cis isomer?" permits a number of answers, relating to various aspects of the chemistry of the two compounds, but the crucial one concerning antitumor activity is yet to be answered. In principle, any of the following reasons or combinations thereof might account for the observed differences in biological effects, but some are more likely than others: 1. TARGET MOLECULES: It is generally accepted that DNA is the most important target molecule of cisplatin and that inhibition of DNA synthesis correlates with antitumor activity. This fact does not contradict observations on extensive reaction with other biomolecules. The mutagenic effects of trans-a2Pt(II), although weaker than for cis-DDP, point toward DNA as being an important target for trans-DDP as well. 2. DNA ADDUCTS: As a consequence of the inherent difference in geometry, the two isomers form different adducts. Specifically, trans-DDP cannot form 1,2-intrastrand crosslinks, which represent by far the most abundant adducts of cis-DDP. On the other hand, the trans isomer displays a greater variation in nucleobase donor sites (cf. Sec. 4.2). 3. DNA STABILITY: While the 1,2-intrastrand adducts of cis-DDP, regardless if GG or AG, consistently cause DNA kinking and lead to thermal destabilization, the effects of trans-DDP adducts seem to be of a greater variability, causing thermal stabilization or destabilization. For intrastrand 1,3 adducts in puXpu sequences, the intervening base X appears to be important in this respect (cf. Sec. 4.3). 4. DNA REPAIR: In living cells, higher doses of trans-DDP as compared to cis-DDP are required to bind an equal number of Pt atoms per nucleotide [66]. On the other hand, bifunctional DNA adducts of either isomer inhibit DNA replication to the same extent [66,150,151]. This finding has been interpreted in terms of a differential repair of adducts of the two isomers [66], but an alternative explanation has also been offered [152]. It is to be noted that repair of monofunctional trans-DDP lesions does not require enzymatic repair but rather may be accomplished by any nucleophile within the cell exercising a reasonably high trans influence, e.g., an S-donor of glutathione. 5. INTRINSIC REACTIVITY: Differences in hydrolysis kinetics of the two isomers (unfavorable equilibrium concentration of trans-[(NH3)2Pt-Cl(OH2)]+ [37]) and in reaction rates of various hydrolysis species with DNA constituents [36] could, in principle, explain a difference in biological effects. On the other hand, the kinetics of reactions of the dichloro species of both isomers with DNA (in the absence of any repair agents) appear not to be that largely different to produce a strong point for differential reactivity of this species. Model studies have shown at least one more distinct difference between mono(nucleobase) adducts of both isomers: While cis-[a2PtLCl]+ can lose the amine trans to Cl, in trans-[a2PtLCl]+ Cl is capable of displaying L (cf. Sec. 6.1). Both reactions are not very fast with Cl-, but any good nucleophile replacing Cl- would do so with high efficiency. In the case of trans-DDP, such a reaction leads to removal of Pt from DNA, unlike in the case of cis-DDP (even though we are aware that cis effects may also be operative). With respect to amine displacement from monoadducts of cis-DDP, it is interesting to speculate on the fate of (toxic) NH3. Is it capable of undergoing condensation reactions with biomolecules? In theory, such a scenario might provide possibilities for the role of the amine ligands in cis-(amine)2Pt(II) compounds alternative to those commonly accepted (e.g., role of NH protons in stabilizing DNA adducts [153]). 6. TRANSPORT AND DISTRIBUTION: Despite differences in water solubility of the two isomers (trans-DDP less soluble), this property is unlikely to be important at physiological concentrations...