DNA Topoisomerase I-mediated DNA Cleavage and Cytotoxicity of Camptothecin Analogues

Yaw Huei Hsiang, Leroy F. Liu, Monroe E. Wall, Mansukh C. Wani, Allan W. Nicholas, Govindar Manikumai, Stanley Kirschenbaum, Robert Silber, Milan Potmesil

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409 引文 斯高帕斯(Scopus)


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.

頁(從 - 到)4385-4389
期刊Cancer Research
出版狀態已發佈 - 8月 15 1989

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究


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