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Science 10 September 1999:
Vol. 285. no. 5434, pp. 1733 - 1737
DOI: 10.1126/science.285.5434.1733
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Reports

A Chemical Inhibitor of p53 That Protects Mice from the Side Effects of Cancer Therapy

Pavel G. Komarov, 12* Elena A. Komarova, 1* Roman V. Kondratov, 15 Konstantin Christov-Tselkov, 3 John S. Coon, 2 Mikhail V. Chernov, 4 Andrei V. Gudkov 1dagger

Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Because these effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to prevent damage of normal tissues during treatment of p53-deficient tumors. To test this possibility, a small molecule was isolated for its ability to reversibly block p53-dependent transcriptional activation and apoptosis. This compound, pifithrin-alpha , protected mice from the lethal genotoxic stress associated with anticancer treatment without promoting the formation of tumors. Thus, inhibitors of p53 may be useful drugs for reducing the side effects of cancer therapy and other types of stress associated with p53 induction.

1 Department of Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
2 Department of Pathology, Rush Presbyterian St. Luke's Medical Center, Chicago, IL 60612, USA.
3 Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.
4 Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
5 Quark Biotech, Pleasanton, CA 94566, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: gudkov{at}uic.edu

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Nuclear Translocation of Nuclear Transcription Factor-kappa B by alpha -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors Leads to Transcription of p53 and Cell Death in Dopaminergic Neurons.
G. A. de Erausquin, K. Hyrc, D. A. Dorsey, D. Mamah, M. Dokucu, D. H. Masco, T. Walton, K. Dikranian, M. Soriano, J. M. G. Verdugo, et al. (2003)
Mol. Pharmacol. 63, 784-790
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Short-term injection of antiapoptotic cytokine combinations soon after lethal gamma -irradiation promotes survival.
F. Herodin, P. Bourin, J.-F. Mayol, J.-J. Lataillade, and M. Drouet (2003)
Blood 101, 2609-2616
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