Interaction of trans-Diamminedichloroplatinum(II) with DNA: Formation of Monofunctional Adducts and Their Reaction with Glutathione

Bifunctional reactions with DNA are responsible for the toxic action of the cancer chemothen apeutic drug cis-diamminedichloroplatinum(II) (cis-DDP). Thiourea has previously been used to tra transient monofunctional adducts in DNA before they rearrange to the toxic lesions. In these studies, thioure was used to quantify the monofunctional adducts produced by the ineffective isomer trans-DDP. Rathe than trapping monofunctional adducts, thiourea labilized them from DNA. At short time periods, 85 of trans-DDP bound to double-stranded DNA as monofunctional adducts of deoxyguanosine. Rearrangemen to bifunctional adducts in double-stranded DNA was 50% complete in 24 h but was much more rapid i single-stranded DNA with 100% complete rearrangement in 24 h. The ineffectiveness of trans-DDP therefore results from a high proportion of monofunctional adducts in DNA that rearrange very slowly to toxi bifunctional adducts. The persistent monofunctional adducts react rapidly with glutathione, which woul further reduce their potential toxicity by preventing them from rearranging to more toxic bifunctional adducts.