DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues

Y. H. Hsiang, Leroy-Fong Liu, M. E. Wall, M. C. Wani, A. W. Nicholas, G. Manikumar, S. Kirschenbaum, R. Silber, M. Potmesil

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Abstract

20(S)-Camptothecin, the 20(S)-camptothecin sodium salt, and 12 analogues with substituents on the A ring differ widely in their effectiveness in the treatment of murine L1210 lymphoblastic leukemia in vivo. The drugs were screened in the following systems: System 1, the cleavage of DNA in the presence of purified topoisomerase I; System 2, drug-induced trapping of topoisomerase I in a covalent complex with DNA; and System 3, the induction of protein-associated DNA breaks in drug-treated L1210 leukemia cells. 9-Amino-20(S), 10-amino-20(RS), and 10,11-methylenedioxy-20(RS), drugs effective against murine L1210 leukemia in vivo, stabilize topoisomerase I-DNA cleavable complexes in a purified system and in cultured L1210 cells. Other analogues, inactive against L1210 leukemia in vivo, were totally ineffective in topoisomerase I-directed screens. The rest of the analogues were intermediate in terms of their antitumor and topoisomerase I-directed activities. The study shows that the drug-induced accumulation of enzyme-DNA cleavable complexes is directly proportional to drug cytotoxicity and antitumor activity.

Original languageEnglish
Pages (from-to)4385-4389
Number of pages5
JournalCancer Research
Volume49
Issue number16
Publication statusPublished - 1989
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hsiang, Y. H., Liu, L-F., Wall, M. E., Wani, M. C., Nicholas, A. W., Manikumar, G., Kirschenbaum, S., Silber, R., & Potmesil, M. (1989). DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues. Cancer Research, 49(16), 4385-4389.