The reactions of cis-[Pt(NH3)2(H2O)2]2+ with L-(+)-cystathionine and seleno-L-methionine: potential relevance to the molecular basis of cisplatin toxicity.

NMR spectroscopic studies indicate that the hydrolysis product of cisplatin, cis-[Pt(NH3)2-(H2O)2]2+, reacts readily with the important intracellular thiol L-(+)-cystathionine and the amino acid derivative seleno-L-methionine. In both cases, the formation of six-membered mononuclear S,N- or Se, N-chelate rings was established on the basis of [1H], [13C], [77Se], [195Pt], and [13C]-(1H) DEPT (distortionless enhancement by polarization transfer), COSY (correlation spectroscopy), heterocorrelation, and NOE (nuclear Overhauser effect) difference NMR experiments. The formation of these products suggests that related in vivo processes may play a significant role in the toxicity of cisplatin. The potential loss of NH3 in such platinum complexes may lead to additional products over time.

An in vitro model for the in vivo mobilization of cadmium by chelating agents using 113Cd-NMR spectroscopy.

An in vitro method, based on 113Cd-NMR spectroscopy, that provides an alternative to the use of animals for an initial screening of cadmium antagonists is presented. The relative values of the effective stability constants of potential chelating antagonists for cadmium are estimated by using 113Cd-NMR spectroscopy to determine the concentrations of the cadmium species involved in appropriate competitive equilibria. This is accomplished via an examination of the competition between the proposed antagonist and EDTA (ethylenediaminetetraacetic acid) for cadmium-113; previously, EDTA has been shown to be capable of removing cadmium from such in vivo binding sites as metallothionein. The reactions proceed via the stepwise addition of three dithiocarbamate groups to the cadmium accompanied by the concurrent stepwise release of donor groups from the EDTA. The resulting 113Cd-NMR data allow for the determination of the overall stability constant for the complex formed between cadmium and N-methyl-D-glucamine dithiocarbamate, iminodiacetic acid dithiocarbamate, proline dithiocarbamate, sarcosine dithiocarbamate. The use of 113Cd-NMR spectroscopy has the potential for providing direct evidence on the effectiveness of chelate antagonists to compete with endogenous ligands for other toxic metal ions. This technique could prove very useful for other compounds that are not stable enough toward acid and/or base to be examined by standard titrimetric methods.

The relative nephrotoxicity of cisplatin, cis-[Pt(NH3)2(guanosine)2]2+, and the hydrolysis product of cisplatin in the rat.

An examination of the comparative nephrotoxicity in the rat of cisplatin, its hydrolysis product (mostly cis-[Pt(NH3)2Cl(H2O)]+ under the conditions applied), and cis-[Pt(NH3)2(guanosine)2]2+ revealed that these compounds differed significantly in the extent of renal damage they produced following their i.v. injection in Sprague-Dawley rats. The hydrolysis product was found to be the most toxic of the three complexes studied and produced nephrotoxicity at doses lower than those at which cisplatin was nephrotoxic. Under the conditions used, the i.v. administration of cis-[Pt(NH3)2(guanosine)2]2+ resulted in no observable signs of nephrotoxicity at levels at which an equimolar dose of cisplatin produces clear evidence of renal function impairment and morphological alterations. The nephrotoxicity of these complexes appears to be generally related to the ease with which they undergo nucleophilic substitution reactions. The lack of substantial nephrotoxicity found for cis-[Pt(NH3)2(guanosine)2]2+ suggests that the products resulting from the action of the DNA repair processes on platinated DNA do not contribute significantly to the nephrotoxicity of cisplatin. Renal platinum levels found following the administration of these compounds correlated with the degree of nephrotoxicity produced by each compound, but no general correlation of nephrotoxicity and renal platinum levels was found. The nephrotoxicity of cis-[Pt(NH3)2Cl(H2O)+ on a molar basis was estimated to be approximately 3 times as great as that of cisplatin itself.