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Molecular Pharmacology

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Research ArticleArticle

Studies on Camptothecin:

I. Effects on Nucleic Acid and Protein Synthesis

SUSAN B. HORWITZ, CHUNG-KE CHANG and ARTHUR P. GROLLMAN
Molecular Pharmacology November 1971, 7 (6) 632-644;
SUSAN B. HORWITZ
Departments of Pharmacology and Medicine and Division of Biology, Albert Einstein College of Medicine, New York, New York 10461
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CHUNG-KE CHANG
Departments of Pharmacology and Medicine and Division of Biology, Albert Einstein College of Medicine, New York, New York 10461
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ARTHUR P. GROLLMAN
Departments of Pharmacology and Medicine and Division of Biology, Albert Einstein College of Medicine, New York, New York 10461
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Abstract

The plant alkaloid camptothecin inhibits the synthesis of DNA and RNA in HeLa cells at concentrations that do not initially influence protein synthesis. DNA, isolated from cells inhibited by camptothecin, has a sedimentation constant of approximately 40 S under alkaline conditions, in contrast to the high molecular weight DNA found in untreated cells. Inhibition of RNA synthesis in intact cells is completely reversed by removing the antibiotic from the medium, while DNA synthesis is only partially reversed by this procedure. Camptothecin does not significantly inhibit activity of the DNA-dependent RNA polymerase isolated from Escherichia coli or of DNA and RNA polymerases prepared from HeLa cells. The structure-activity relationships of camptothecin and its analogues, as determined by their effects on nucleic acid synthesis in HeLa cells and on the sedimentation of DNA obtained from drug-treated cells, correspond closely to their activity in suppressing the growth of tumors in experimental animals. The inhibitory effects of camptothecin on nucleic acid synthesis may account for its chemotherapeutic properties, and the reversibility of the effects on RNA synthesis suggests that camptothecin may be a useful tool for the study of macromolecular synthesis in animal cells.

ACKNOWLEDGMENTS We are grateful to Drs. M. Wall and M. C. Wani for providing us with the samples of camptothecin and its analogues. We are indebted to Drs. M. Wall, A. S. Kende, and J. Hurwitz for helpful discussions, and thank Drs. D. Kessel and M. Horwitz for informing us of their experimental results prior to publication. Dr. M. T. Huang determined the effects of camptothecin on leucine incorporation in lysates prepared from rabbit reticulocytes.

  • Copyright ©, 1971, by Academic Press, Inc.

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Molecular Pharmacology
Vol. 7, Issue 6
1 Nov 1971
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Research ArticleArticle

Studies on Camptothecin:

SUSAN B. HORWITZ, CHUNG-KE CHANG and ARTHUR P. GROLLMAN
Molecular Pharmacology November 1, 1971, 7 (6) 632-644;

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Research ArticleArticle

Studies on Camptothecin:

SUSAN B. HORWITZ, CHUNG-KE CHANG and ARTHUR P. GROLLMAN
Molecular Pharmacology November 1, 1971, 7 (6) 632-644;
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