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JNCI Journal of the National Cancer Institute 2000 92(24):1999-2008; doi:10.1093/jnci/92.24.1999
© 2000 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 92, No. 24, 1999-2008, December 20, 2000
© 2000 Oxford University Press

Protection of Normal Proliferating Cells Against Chemotherapy by Staurosporine-Mediated, Selective, and Reversible G1 Arrest

Xiaomei Chen, Michael Lowe, Thaddeus Herliczek, Michael J. Hall, Christopher Danes, David A. Lawrence, Khandan Keyomarsi

Affiliations of authors: X. Chen, M. Lowe, T. Herliczek, C. Danes (Laboratory of Diagnostic Oncology), M. J. Hall (Laboratory of Clinical and Experimental Endocrinology and Immunology), Division of Molecular Medicine, Wadsworth Center, Albany, NY; D. A. Lawrence, Laboratory of Clinical and Experimental Endocrinology and Immunology, Division of Molecular Medicine, Wadsworth Center, and Department of Biomedical Sciences, State University of New York, Albany; K. Keyomarsi, Laboratory of Diagnostic Oncology, Division of Molecular Medicine, Wadsworth Center, and Department of Biomedical Sciences, State University of New York, Albany.

Correspondence to present address: Khandan Keyomarsi, Ph.D., Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Box 66, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: kkeyomar{at}mdanderson.org).

Background: A major limiting factor in human cancer chemotherapy is toxicity in normal tissues. Our goal was to determine whether normal proliferating cells could be protected from chemotherapeutic agents by taking advantage of the differential drug sensitivity of cell cycle G1 checkpoint in normal and cancer cells. Methods: Normal mammary epithelial cells and mammary cancer cells were initially treated with staurosporine at a cytostatic (i.e., nonlethal) concentration, which preferentially arrests normal cells in the G0/G1 phase of the cell cycle without affecting the proliferation of tumor cells. After the selective arrest of normal cells in G0/G1, both normal and tumor cells were treated with doxorubicin or camptothecin, two cytotoxic (i.e., lethal) chemotherapeutic agents. Cells were then allowed to recover in drug-free medium for 12 days. Results: After pretreatment of both normal and tumor cells with staurosporine followed by treatment with doxorubicin or camptothecin, tumor cells were selectively killed by chemotherapeutic agents, whereas normal cells resumed proliferation after the drugs were removed. Pretreatment with staurosporine also protected normal circulating lymphocytes that had been induced to proliferate in vitro with phytohemagglutinin from chemotherapeutic agents. Staurosporine-induced arrest of normal cells in G0/G1 phase was reversible, and arrested cells tolerated doses of camptothecin that were more than 100-fold higher than necessary to eradicate all tumor cells in culture. Staurosporine-mediated G0/G1 arrest targets the retinoblastoma protein (pRb) pathway and was accompanied by a rapid decrease in cyclin-dependent kinase (CDK) 4 protein levels, increased binding of CDK inhibitors p21 and p27 to CDK2, and inhibition of CDK2 activity in normal cells. Conclusions: Breast cancer cells with defective checkpoints regulated by the pRb pathway can be targeted specifically with chemotherapeutic agents, following staurosporine-mediated, selective and reversible G0/G1 arrest in normal cells.


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