Mechanism of Interaction of CC-1065 (NSC 298223) with DNA

David H. Swenson, Li H. Li, Gary L. Petzold, Brian D. Dayton, Tanya L. Wallace, Alice H. Lin, William C. Krueger, Laurence H. Hurley, J. Stefan Rokem

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Abstract

CC-1065 (NSC 298223), a potent new antitumor antibiotic produced by Streptomyces zelensis, interacts strongly with double-stranded DNA and appears to exert its cytotoxic effects through disruption of DNA synthesis. We undertook this study to elucidate the sites and mechanisms of CC-1065 interaction with DNA. The binding of CC-1065 to synthetic and native DNA was examined by differential circular dichroism or by Sephadex chromatography with photometric detection. The binding of CC-1065 with calf thymus DNA was rapid, being complete within 2 hr, and saturated at 1 drug per 7 to 11 base pairs. The interaction of CC-1065 with synthetic DNA polymers indicated a specificity for adenine- and thymine-rich sites. Agarose gel electrophoresis of CC-1065-treated supercoiled DNA showed that CC-1065 did not intercalate. Site exclusion studies using substitutions in the DNA grooves showed CC-1065 to bind primarily in the minor groove. CC-1065 did not cause DNA breaks; it inhibited susceptibility of DNA to nuclease Si digestion. It raised the thermal melting temperature of DNA, and it inhibited the ethidium-induced unwinding of DNA. Thus, in contrast to many antitumor agents, CC-1065 stabilized the DNA helix. DNA helix overstabilization may be relevant to the mechanism of action of CC-1065. 9, 2016.

Original languageEnglish (US)
Pages (from-to)2821-2828
Number of pages8
JournalCancer Research
Volume42
Issue number7
StatePublished - Jul 1 1982

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Swenson, D. H., Li, L. H., Petzold, G. L., Dayton, B. D., Wallace, T. L., Lin, A. H., Krueger, W. C., Hurley, L. H., & Rokem, J. S. (1982). Mechanism of Interaction of CC-1065 (NSC 298223) with DNA. Cancer Research, 42(7), 2821-2828.