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DNA Supercoiling, Shortening, and Induction of Single-Strand Regions by cis-Diamminedichloroplatinum(II)¹

Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030 [S. M., Y. D., A. W. P., S. T. C.]; Bristol Laboratories, Syracuse, New York 13201 [A. W. P.]; and Smith, Kline & French Laboratories, Philadelphia, Pennsylvania 19101 [S. T. C.]

cis-Diamminedichloroplatinum(II) was found to bind to covalently closed circular supercoiled, covalently closed circular nonsupercoiled, and single-strand broken relaxed PM2 DNA and induce different types of DNA conformational changes. Using Kleinschmidt's technique, it was found that binding of cis-diamminedichloroplatinum(II) decreased the DNA length to 75% of the original single-strand broken relaxed DNA without inducing superhelical conformational changes. cis-Diamminedichloroplatinum(II) also shortened the length of covalently closed circular nonsupercoiled DNA before a supercoiled conformation was generated.

Single strand-specific nucleases were used to detect drug-induced DNA structural alterations. Local single-strand regions or regions of denaturation were detected by S1 nuclease from Aspergillus oryzae and by BAL-31 nuclease from Alteromonas espejiana BAL-31. The single-strand regions or local denaturation regions do not seem to be related to or caused by DNA superhelical conformational changes since they were detected at drug concentrations at which no significant DNA superhelical turns were found. DNA shortening, superhelical conformational changes, and local denaturation regions can be explained by the previously proposed "DNA intrastrand cross-linking" model (Stone et al., J. Mol. Biol., 104: 793–801, 1976).

¹ Research supported by a grant from Bristol Laboratories, Syracuse, N. Y., and by Grant CA-10843-P12 from the National Cancer Institute.

² Predoctoral trainee. To whom requests for reprints should be addressed, at Bristol-Baylor Laboratory, Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.

Received 3/16/81. Accepted 7/ 7/81.

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