Modifications of natural DNA in a cell-free medium by dinuclear bisplatinum complexes with equivalent coordination spheres, represented by the general formula [
{ ~~U~~-P~C~(NH,),),(H,N-R-NH,)]~+,where R is a propane or hexane, were studied by various methods of biochemical analysis or molecular biophysics. These methods include binding studies by means of differential-pulse polarography, measurements of melting curves with the aid of absorption spectrophotometry, measurements of CD spectra, ELISA with specific antibodies that recognize DNA modified by platinum complexes, interstrand crosslinking assay employing gel electrophoresis under denaturing conditions and mapping of DNA adducts by means of transcription assays. The results indicated that the major adduct of [ ( trans-PtCl(NH,),),(H,N-R-NH,)],' in DNA was an interstrand cross-link which was formed with a relatively short half-time ( = l h).At least some types of these interstrand cross-links induced local denaturational changes in the DNA. The results of analyses of interactions of [ { trans-PtCl(NH,),) ,(H,N-R-NH,)]2+ with linear DNA at relatively higher levels of the modification could be interpreted to mean that these dinuclear platinum complexes were also capable of intrastrand-cross-link formation between adjacent base residues in DNA. [Farrell, N. (1991) in Plutinum and other metal coordination compounds in cancer chemotherapy (Howell, S. B., ed.) pp. 81-91, Plenum Press, New York] that the binding of the dinuclear platinum complexes modifies DNA in a way that is different from the modification by antitumor cisplatin. Thus, the results of this work are consistent with the hypothesis that platinum drugs that bind to DNA in a manner fundamentally different from that of cisplatin can exhibit altered biological properties, including a different spectrum and intensity of antitumor activity.
However, these intrastrand adducts of [ { ~~U~~-P~C~(NH,),},(H,N-R-NH,)]~'Keywords: DNA ; platinum drug ; dinuclear complex ; cross-link; anticancer effect. Fig. 1 A) and its analogue cis-diammine( 1,l-cyclobutyldicarboxy1ato)platinum(1I) (carboplatin) are effective anticancer drugs approved for the treatment of several human malignancies (Loehrer and Einhom, 1984;Harrap et al., 1985). Even though these platinum drugs are among the most successful antitumor compounds developed in recent years, they display limited activity against some of the common forms of the disease, such as colon and breast cancers. In addition, a variety of adverse effects, and acquired resistance are observed in patients receiving cisplatin or carboplatin chemotherapy. These limitations have inspired efforts to develop new platinum-based drugs that display improved therapeutic properties. One approach to this problem is to identify new classes of antitumor-active platinum complexes that have structural features that differ from those of the cisplatin analogues tested. Exploring new structural classes of platinum antitumor drugs resulted in the discovery of dinuclear bisplatinum complexes wit...
