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Interaction of cis-Diamminedichloroplatinum(II) with PM-2 DNA¹

Bristol-Baylor Laboratory, Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030 [S. M., C. H. H., A. W. P., S. T. C.], and Bristol Laboratories, Syracuse, New York 13201 [A. W. P., S. T. C.]

The interaction of cis-diamminedichloroplatinum(II) (CDDP) with PM-2 DNA was studied using two techniques: (a) agarose gel electrophoresis of PM-2 DNA conformation isomers after CDDP binding; and (b) viscometric measurement of different forms of CDDP-bound PM-2 DNA. In both systems, the results indicated that the DNA isomers interacted differently with CDDP. CDDP induced a decrease of viscosity upon interacting with single-strand broken relaxed circular (Form II) and double-strand broken linear (Form III) PM-2 DNA's. These observations are consistent with a "DNA shortening effect" proposed by Cohen et al. [Science (Wash. D. C.), 203: 1014–1016, 1979] and Macquet et al. [Biochimie (Paris), 60: 901–914, 1978].

When covalently closed circular (Form I) PM-2 DNA was used, increasing concentrations of CDDP induced an initial slight increase and then decrease of electrophoretic mobility to the degree that it comigrated with CDDP-bound Form II DNA. Further addition of CDDP restored the electrophoretic mobility of Form I DNA. Corresponding changes in the viscosity of CDDP-bound Form I DNA showed an initial decrease, then an increase, and a final prolonged decrease of viscosity. These effects are similar but not identical to those induced by either DNA intercalators (e.g., ethidium bromide) or certain DNA denaturating agents (e.g., formaldehyde, ultraviolet light, alkali trichloroacetate, methylmercuric hydroxide, and carbodiimide). Thus, CDDP may induce a DNA superhelix-unwinding process followed either by rewinding or a denaturation process or both.

Quantitative analysis of the agarose gel electrophoretic pattern plus sucrose density gradient centrifugation studies also indicated that there was little DNA strand breakage induced by CDDP treatment.

¹ Research reported in this paper was supported by Bristol Laboratories.

² Predoctoral trainee supported by Baylor College of Medicine Institutional Funds. To whom requests for reprints should be addressed.

³ Recipient of Grant CA-10985-10 from the National Cancer Institute.

Received 2/18/80. Accepted 6/ 5/80.

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