To study the possible reversibility of platinum-protein binding, the platinum-methionine and platinum-cysteine model adducts cis-[Pt(NH3)(2)(GSMe)(2)](2+), [Pt(dien)(GSMe)](2+), [Pt(dien)(GS)](+), and {[Pt(dien)](2)(GS)}(3+) (GSH = glutathione, GSMe = S-methylglutathione) have been reacted with 5'-AMP and 5'-GMP and d(GpC) under a variety of reaction conditions. Only 5'-GMP and d(GpG) were found to substitute GSMe (a Pt-thioether bond) from [Pt(dien)(GSMe)](2+), forming [Pt(dien)(GMP-N7)](2+) and {Pt(dien)[d(GpG)-N7)]}(2+), respectively. Reacting the GSMe diadduct of cisplatin [cis-Pt(NH3)(2)(GSMe)(2)](2+) with GMP revealed that the N7 of 5'-GMP can also substitute GSMe on cisplatin, forming cis-[Pt(NH3)(2)(GSMe)(GMP-N7)](2+) and the GMP diadduct cis-[Pt(NH3)(2)(GMP-N7)(2)](2+). The platinum-cysteine model adducts [Pt(dien)(GS)](+) and {[Pt(dien)](2)(GS)}(3+), however, did not react with 5'-AMP or 5'-GMP at 37 degrees C. Kinetic experiments have revealed that the intermolecular rearrangement reaction of Pt(dien)(2+) from thioether sulfur to 5'-GMP is second order and that the reaction is slow at ambient temperature (t(1/2) = 179 h). At 35 degrees C the reaction proceeds with a reaction rate (t(1/2) = 31 h), which appears as a relevant rate for in vivo processes. The obtained results are discussed in relation to the antitumor activity and toxicity of platinum complexes. The data suggest that the existence of a drug reservoir is limited to platinum-thioether-type adducts and that the observed rearrangement only occurs with the N7 of guanine and not with adenine. Consequently, new platinum amine chelate complexes in which a thioether function is present as a leaving group might be successful as platinum antitumor compounds exhibiting reduced toxic side effects.