Sensitization of Tumors to Chemotherapy Through Gene Therapy
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SENSITIZATION OF TUMORS TO CHEMOTHERAPY THROUGH GENE THERAPY Ruth A. Gjerset and Dan Mercola Sidney Kimmel Cancer Center 10835 Altman Row San Diego, California 92121
1. INTRODUCTION The cellular response to DNA damage plays a critical role not only in tumor progression but also in the process of acquired drug resistance, a problem that affects about half of all cancer cases overall and remains one of the major obstacles to successful therapy of cancer. Modulation of these DNA damage response pathways may therefore provide us with a means to reverse acquired drug resistance and improve the outcome of therapy for a large fraction of cancer patients. In this article we will focus on two major pathways involved in the cellular response to DNA damage: The Jun kinase stress activated pathway, and the p53-mediated DNA damage response pathway leading to apoptosis. Through independent mechanisms, each of these pathways modulates the cellular response to DNA damaging chemotherapies and radiation. Therapeutic approaches based on inhibiting the Jun kinase pathway and/or restoring the p53 pathway may, therefore, provide us with new biological strategies for reversing acquired drug resistance, thus improving the outcome of therapy for most cancers.
2. THE p53 TUMOR SUPPRESSOR AND THE DNA DAMAGE RESPONSE Over half of all cancers suffer loss of function of the p53 tumor suppressor (Levine, 1993), a key player in the induction of apoptosis in response to DNA damage (Clarke et al., 1993; Gjerset et al., 1995; Lotem et al., 1993; Lowe et al., 1993), in addition to its roles in cell cycle regulation and DNA repair (Levine, 1997). Its involvement in DNA damage-induced apoptosis may derive from its ability to bind, alone or possibly in combination with other DNA damage recognition proteins, to sites of damaged DNA, including single stranded ends and insertion-deletion loops (Bakalkin et al., 1995; Lee et al., 1995; Levine 1997 (review)). p53 might also bind to DNA adducts and strand breaks induced by various therapies. The frequent loss of p53 function in Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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cancer, often associated with disease progression and increased genomic instability, may reflect at least in part the role of p53 in DNA damage recognition and apoptosis. Most genome destabilizing events, including gene amplification, gene deletion and gene translocation, involve DNA strand breaks (Stark, 1993). These breaks could serve as triggers for p53-mediated apoptosis and provide the driving force for loss of p53. The same process that underlies the progression of cancer, that is, genomic instability accompanied by loss of p53-mediated apoptosis, can also lead to therapy resistance. Support for the idea that loss of p53 could desensitize a cell to the damaging effects of drugs and radiation comes from studies of p53-null transgenic mice. In these studies it was observed that normal transgenic hematopoietic ce
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