Modeling the Therapeutic Efficacy of P53 Restoration in Tumors.
From: Cancer Research Institute and Department of Cellular and Molecular Pharmacology, Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell
- Publish Date: Dec 2006
- ISSN: 0092-8674
- Volume: 127
- Issue: 7
- Pages: 1323-34
- Medium: Print
- Language: English
- Citation (JAMA): Martins Carla P, Brown-Swigart Lamorna, Evan Gerard I, et al. Modeling the Therapeutic Efficacy of P53 Restoration in Tumors.. Cell Dec 2006;127:1323-34
Abstract
Although restoration of p53 function is an attractive tumor-specific therapeutic strategy, it remains unclear whether p53 loss is required only for transition through early bottlenecks in tumorigenesis or also for maintenance of established tumors. To explore the efficacy of p53 reinstatement as a tumor therapy, we used a reversibly switchable p53 knockin (KI) mouse model that permits modulation of p53 status from wild-type to knockout, at will. Using the well-characterized Emu-myc lymphoma model, we show that p53 is spontaneously activated when restored in established Emu-myc lymphomas in vivo, triggering rapid apoptosis and conferring a significant increase in survival. Nonetheless, reimposition of p53 function potently selects for emergence of p53-resistant tumors through inactivation of p19(ARF) or p53. Our study provides important insights into the nature and timing of p53-activating signals in established tumors and how resistance to p53 evolves, which will aid in the optimization of p53-based tumor therapies.
Mesh Headings (Keywords): Alleles, Animals, DNA Damage, Gene Dosage, Lymphoma, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neoplasm Transplantation, Proto-Oncogene Proteins c-myc, Signal Transduction, Tumor Suppressor Protein p53
Check for Full Text / PubMed Unique Identifier (PMID): 17182091
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