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

Research output: Contribution to journalArticle

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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

Fingerprint

Camptothecin
Type I DNA Topoisomerase
DNA Cleavage
Leukemia L1210
Pharmaceutical Preparations
DNA Breaks
DNA
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Antineoplastic Agents
Cultured Cells
Salts
Sodium
Enzymes
Proteins

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., ... Potmesil, M. (1989). DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues. Cancer Research, 49(16), 4385-4389.

DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues. / Hsiang, Y. H.; Liu, Leroy-Fong; Wall, M. E.; Wani, M. C.; Nicholas, A. W.; Manikumar, G.; Kirschenbaum, S.; Silber, R.; Potmesil, M.

In: Cancer Research, Vol. 49, No. 16, 1989, p. 4385-4389.

Research output: Contribution to journalArticle

Hsiang, YH, Liu, L-F, Wall, ME, Wani, MC, Nicholas, AW, Manikumar, G, Kirschenbaum, S, Silber, R & Potmesil, M 1989, 'DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues', Cancer Research, vol. 49, no. 16, pp. 4385-4389.
Hsiang YH, Liu L-F, Wall ME, Wani MC, Nicholas AW, Manikumar G et al. DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues. Cancer Research. 1989;49(16):4385-4389.
Hsiang, Y. H. ; Liu, Leroy-Fong ; Wall, M. E. ; Wani, M. C. ; Nicholas, A. W. ; Manikumar, G. ; Kirschenbaum, S. ; Silber, R. ; Potmesil, M. / DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues. In: Cancer Research. 1989 ; Vol. 49, No. 16. pp. 4385-4389.
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