CHEMICAL VERSATILITY OF TRANSPLATIN MONOFUNCTIONAL ADDUCTS WITHIN MULTIPLE SITE-SPECIFICALLY PLATINATED DNA

The first step of the reaction between DNA and the antitumor drug cisp latin or its clinically inactive isomer transplatin yields monofunctio nal adducts, Most of the cisplatin monofunctional adducts further reac t and rather rapidly (t(1/2) smaller than a few hours) to form intrast rand and interstrand crosslinks. It is generally accepted that the cli nical activity of cisplatin is related to the formation of bifunctiona l lesions, As concerns transplatin, several studies disagree on the ra te of closure of the monofunctional adducts and the nature of the bifu nctional lesions, In order to explain these discrepancies, we have pre pared several duplexes containing a single monofunctional trans-[Pt(NH 3)(2)(dG)Cl](+) adduct and zero to two monofunctional [Pt(dien)(dG)](2 +) adducts at defined positions. In these duplexes, the inert [Pt(dien )(dG)](2+) adducts mimic the presence of transplatin monofunctional ad ducts, We show that the closure of the transplatin monofunctional addu cts is strongly affected by the presence of other adducts and by the l ength of the duplexes. These findings suggest that the discrepancies i n the literature originate from the nature of the platinated samples ( molar ratio of bound platinum per nucleotide, length of the DNA fragme nts). Our general conclusion is that within transplatin-modified DNA, at a low level of platination, the monofunctional adducts evolve slowl y (t(1/2) > 24 h) into bifunctional lesions and that these bifunctiona l lesions are mainly interstrand cross-links, This could explain, at l east in part, the clinical inefficiency of transplatin.