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 Kharbanda, S. Articles by Kufe, D. Search for Related Content PubMed PubMed Citation Articles by Kharbanda, S. Articles by Kufe, D.

Camptothecin and Its Derivatives Induce Expression of the c-jun Protooncogene in Human Myeloid Leukemia Cells¹

Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [S. K., E. R., H. G., D. K.], and The Stehlin Foundation for Cancer Research, The Cancer Research Laboratory, St. Joseph Hospital, Houston, Texas 77002 [H. H., B. G., P. P.]

We have recently demonstrated that certain camptothecin derivatives are effective agents in the treatment of human tumor xenografts in nude mice. While camptothecin and its derivatives are recognized as inhibitors of topoisomerase I, little is known about the effects of these agents on specific gene expression, particularly genes involved in growth control. The c-jun early response gene codes for a leucine zipper transcription factor. The present studies demonstrate that 20(S)-camptothecin, 9-amino-20(S)-camptothecin, and 9-nitro-20(S)-camptothecin inhibit the growth of human U-937 myeloid leukemia cells and induce expression of the c-jun gene. c-jun transcripts were increased at 3 h and reached a maximum at 6 h of drug exposure. We also demonstrate that the induction of c-jun gene expression by these agents occurs at the transcriptional level. H7, a nonselective inhibitor of protein kinase C, completely blocked c-jun expression in 20(S)-camptothecin-treated cells, while another protein kinase inhibitor, HA1004, had no detectable effect. Similar findings were obtained for other leucine zipper encoding genes, including jun-B. These results suggest that 20(S)-camptothecin, 9-amino-20(S)-camptothecin, and 9-nitro-20(S)-camptothecin activate a cellular response involving the induction of early response genes. Finally, we demonstrate that induction of c-jun expression occurs in association with internucleosomal DNA fragmentation, a characteristic of programmed cell death.

¹ This investigation was supported by funds from The Stehlin Foundation for Cancer Research, by NIH Grants P01CA50529 (B. G.) and CA42802 (D. K.), and by a Burroughs Wellcome Award in Clinical Pharmacology (D. K.).

Received 6/17/91. Accepted 10/ 4/91.

This article has been cited by other articles:

				R. Chugh, R. Dunn, M. M. Zalupski, J. S. Biermann, V. K. Sondak, J. R. Mace, K. M. Leu, W. F. Chandler, and L. H. Baker Phase II Study of 9-Nitro-Camptothecin in Patients With Advanced Chordoma or Soft Tissue Sarcoma J. Clin. Oncol., May 20, 2005; 23(15): 3597 - 3604. [Abstract] [Full Text] [PDF]

				S. Somasundaram, N. A. Edmund, D. T. Moore, G. W. Small, Y. Y. Shi, and R. Z. Orlowski Dietary Curcumin Inhibits Chemotherapy-induced Apoptosis in Models of Human Breast Cancer Cancer Res., July 1, 2002; 62(13): 3868 - 3875. [Abstract] [Full Text] [PDF]

				R. Garcia-Carbonero and J. G. Supko Current Perspectives on the Clinical Experience, Pharmacology, and Continued Development of the Camptothecins Clin. Cancer Res., March 1, 2002; 8(3): 641 - 661. [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]

				K. Yoshida, R. Weichselbaum, S. Kharbanda, and D. Kufe Role for Lyn Tyrosine Kinase as a Regulator of Stress-Activated Protein Kinase Activity in Response to DNA Damage Mol. Cell. Biol., August 1, 2000; 20(15): 5370 - 5380. [Abstract] [Full Text]

				D. S. Park, E. J. Morris, L. A. Greene, and H. M. Geller G1/S Cell Cycle Blockers and Inhibitors of Cyclin-Dependent Kinases Suppress Camptothecin-Induced Neuronal Apoptosis J. Neurosci., February 15, 1997; 17(4): 1256 - 1270. [Abstract] [Full Text] [PDF]