This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, L. H. Articles by Bhuyan, B. K. Search for Related Content PubMed PubMed Citation Articles by Li, L. H. Articles by Bhuyan, B. K.

Action of Camptothecin on Mammalian Cells in Culture¹

Cancer Research, The Upjohn Company, Kalamazoo, Michigan 49001

Camptothecin (CN) is active against several experimental tumors and has also been studied clinically. We report here the effect of CN on L1210 cells and asynchronous and synchronous DON cells in culture.

CN was toxic both to L1210 cells (0.06 µg/ml, 2-hr exposure) and DON cells (0.15 µg/ml, 1-hr exposure), and it inhibited DNA and RNA synthesis more than it inhibited protein synthesis. CN was more cytotoxic to DON cells in S phase than cells in G₁ or G₂, although it inhibited DNA and RNA synthesis of L1210 cells and asynchronous DON cells almost equally. When asynchronous DON cells were exposed to CN for 30 min and CN was then removed, RNA synthesis was no longer significantly inhibited, but the inhibition of DNA synthesis persisted. The survival patterns of synchronous DON cells were closely related to DNA synthesis inhibition but not to RNA synthesis inhibition. These results collectively suggested that the marked effect of CN on DNA synthesis appeared to be one of the primary determinants of its cytotoxicity. Since no significant effect was observed on the enzymes involved in DNA synthesis, DNA synthesis inhibition by CN may be in part due to its effect on the DNA template. The interaction between CN and DNA was detected by melting point determinations. CN did not block the progression of mitotic cells into S phase. At 100 µg/ml, CN prevented the progression of S phase cells into G₂; at 1 µg/ml, some cells did leave S and proceeded into G₂. Cells in G₂ were blocked from moving into mitosis even at 0.01-µg/ml doses of CN. Thus, the progression of late S or early G₂ cells into mitosis was most sensitive to the drug.

¹ This investigation was supported in part by Contract PH 43-NCI-68-1023 with Drug Research and Development, National Cancer Institute, NIH, Bethesda, Md. 20014.

Received 6/30/72. Accepted 8/23/72.

This article has been cited by other articles:

				F. Koizumi, M. Kitagawa, T. Negishi, T. Onda, S.-i. Matsumoto, T. Hamaguchi, and Y. Matsumura Novel SN-38-Incorporating Polymeric Micelles, NK012, Eradicate Vascular Endothelial Growth Factor-Secreting Bulky Tumors. Cancer Res., October 15, 2006; 66(20): 10048 - 10056. [Abstract] [Full Text] [PDF]

				C. Gomez-Manzano, M. M. Alonso, W.K. A. Yung, F. McCormick, D. T. Curiel, F. F. Lang, H. Jiang, B. N. Bekele, X. Zhou, R. Alemany, et al. Delta-24 Increases the Expression and Activity of Topoisomerase I and Enhances the Antiglioma Effect of Irinotecan Clin. Cancer Res., January 15, 2006; 12(2): 556 - 562. [Abstract] [Full Text] [PDF]

				G. K. Schwartz and M. A. Shah Targeting the Cell Cycle: A New Approach to Cancer Therapy J. Clin. Oncol., December 20, 2005; 23(36): 9408 - 9421. [Abstract] [Full Text] [PDF]

				A. Chatterjee, R. Digumarti, R. N. V. S. Mamidi, K. Katneni, V. V. Upreti, A. Surath, M. L. Srinivas, S. Uppalapati, S. Jiwatani, S. Subramaniam, et al. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of an Orally Active Novel Camptothecin Analog, DRF-1042, in Refractory Cancer Patients in a Phase I Dose Escalation Study J. Clin. Pharmacol., July 1, 2004; 44(7): 723 - 736. [Abstract] [Full Text] [PDF]

				M. Lupi, G. Matera, D. Branduardi, M. D'Incalci, and P. Ubezio Cytostatic and Cytotoxic Effects of Topotecan Decoded by a Novel Mathematical Simulation Approach Cancer Res., April 15, 2004; 64(8): 2825 - 2832. [Abstract] [Full Text] [PDF]

				J. P. Braybrooke, E. Boven, N. P. Bates, R. Ruijter, N. Dobbs, P. D. Cheverton, H. M. Pinedo, and D. C. Talbot Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f ), using a weekly 30-minute intravenous infusion, in patients with advanced solid malignancies Ann. Onc., June 1, 2003; 14(6): 913 - 921. [Abstract] [Full Text] [PDF]

				S. D. Desai, H. Zhang, A. Rodriguez-Bauman, J.-M. Yang, X. Wu, M. K. Gounder, E. H. Rubin, and L. F. Liu Transcription-Dependent Degradation of Topoisomerase I-DNA Covalent Complexes Mol. Cell. Biol., April 1, 2003; 23(7): 2341 - 2350. [Abstract] [Full Text] [PDF]

				M. A. Shah and G. K. Schwartz Cell Cycle-mediated Drug Resistance: An Emerging Concept in Cancer Therapy Clin. Cancer Res., August 1, 2001; 7(8): 2168 - 2181. [Abstract] [Full Text] [PDF]

				A. Loonstra, M. Vooijs, H. B. Beverloo, B. A. Allak, E. van Drunen, R. Kanaar, A. Berns, and J. Jonkers Growth inhibition and DNA damage induced by Cre recombinase in mammalian cells PNAS, July 31, 2001; 98(16): 9209 - 9214. [Abstract] [Full Text] [PDF]

				A. Kuzminov Single-strand interruptions in replicating chromosomes cause double-strand breaks PNAS, July 17, 2001; 98(15): 8241 - 8246. [Abstract] [Full Text] [PDF]

				C. Erlichman, S. A. Boerner, C. G. Hallgren, R. Spieker, X.-Y. Wang, C. D. James, G. L. Scheffer, M. Maliepaard, D. D. Ross, K. C. Bible, et al. The HER Tyrosine Kinase Inhibitor CI1033 Enhances Cytotoxicity of 7-Ethyl-10-hydroxycamptothecin and Topotecan by Inhibiting Breast Cancer Resistance Protein-mediated Drug Efflux Cancer Res., January 1, 2001; 61(2): 739 - 748. [Abstract] [Full Text]

				V. Boige, E. Raymond, S. Faivre, M. Gatineau, K. Meely, S. Mekhaldi, P. Pautier, M. Ducreux, O. Rixe, and J.-P. Armand Phase I and Pharmacokinetic Study of the Camptothecin Analog DX-8951f Administered as a 30-Minute Infusion Every 3 Weeks in Patients With Advanced Cancer J. Clin. Oncol., December 1, 2000; 18(23): 3986 - 3992. [Abstract] [Full Text] [PDF]

				Y. Mao, S. Okada, L.-S. Chang, and M. T. Muller p53 Dependence of Topoisomerase I Recruitment in Vivo Cancer Res., August 1, 2000; 60(16): 4538 - 4543. [Abstract] [Full Text]

				S. Ohdo, T. Makinosumi, T. Ishizaki, E. Yukawa, S. Higuchi, S. Nakano, and N. Ogawa Cell Cycle-Dependent Chronotoxicity of Irinotecan Hydrochloride in Mice J. Pharmacol. Exp. Ther., December 1, 1997; 283(3): 1383 - 1388. [Abstract] [Full Text]

				G. C. Ireton, L. Stewart, L. H. Parker, and J. J. Champoux Expression of Human Topoisomerase I with a Partial Deletion of the Linker Region Yields Monomeric and Dimeric Enzymes That Respond Differently to Camptothecin J. Biol. Chem., August 11, 2000; 275(33): 25820 - 25830. [Abstract] [Full Text] [PDF]

				W. A. Cliby, K. A. Lewis, K. K. Lilly, and S. H. Kaufmann S Phase and G2 Arrests Induced by Topoisomerase I Poisons Are Dependent on ATR Kinase Function J. Biol. Chem., January 4, 2002; 277(2): 1599 - 1606. [Abstract] [Full Text] [PDF]