A Comparative Study on the Interaction of Cis- and Trans-Platin with DNA and RNA

Abstract

Cis-diamminedichloroplatinum(II) is a frequently used and very effective chemotherapeutic drug for treatment of various malignancies; however, the trans isomer is clinically ineffective. Cis-platin exerts its antitumor activity by binding to DNA via intrastrand cross-links to d(GpG) (dG = deoxyguanosine) and to d(ApG) (dA = deoxyadenosine), interfering with DNA replication and transcription and causing cell death. The trans-diamminedichloroplatinum(II) isomer also binds DNA, but is clinically ineffective. This study was designed to examine the interactions of cis- and trans-platin with calf thymus DNA and yeast RNA in aqueous solution at physiological conditions, using a constant DNA and RNA concentration (6.25 mM) and various platin salts/polynucleotide (phosphate) ratios of 1/100, 1/50, 1/25, and 1/12.5. Fourier transform infrared, ultraviolet-visible spectroscopic methods were used to determine the drug binding modes, the binding constants, and the stability of cis- and trans-platin-DNA and -RNA complexes in aqueous solution. Spectroscopic evidence showed that cis- and trans-platin bind to the major and minor grooves of DNA (via G, A, T, and C bases), while RNA binding is through G, U, A, and C bases with some degree of the pt-phosphate (PO(2)) interaction for both isomers and overall binding constants of K((cis-platin-DNA)) = 5.51 x 10(4) M(-1), K((trans-platin-DNA)) = 2.26 x 10(4) M(-1), K((cis-platin-RNA)) = 1.9 x 10(4) M(-1), and K((trans-platin-RNA)) = 1.75 x 10(4) M(-1). DNA and RNA aggregations occurred at high platin concentrations. No biopolymer conformational changes were observed upon cis- and trans-platin interactions, while DNA remains in the B-family, and RNA retains its A-family structure. The order of platin compound-polymer stability was cis-platin-DNA > trans-platin-DNA > cis-platin-RNA > trans-platin-RNA.