Adenovirus-mediated Transfer of a p53 Gene in Ovarian Cancer
Given the lack of effective conventional therapy, those patients with recurrent or refractory ovarian cancer should be considered for currently approved investigational gene therapy protocols. Several studies have shown a potential modality of p53 gene tr
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ADENOVIRUS-MEDIATED TRANSFER OF A p53 GENE IN OVARIAN CANCER
Junzo Kigawa and Naoki Terakawa Departments of Obstetrics and Gynecology Tottori University School of Medicine 36-1 Nishimachi, Yonago 6838504 Japan
1. INTRODUCTION Ovarian cancer, one of the major causes of death from cancer in women, is commonly diagnosed at advanced stage. (Boente et al., 1993; Perez et al., 1993; Thigpen et al., 1993) Cytoreductive surgery followed by platinum-based combination chemotherapy is currently the standard treatment for patients with ovarian cancer. However, the success of treatment is limited by the development of resistance to platinum-based chemotherapy. (Kigawa et al., 1993; Maggie, 1991) As a result, the survival rate for patients with ovarian cancer has been not improved through the past 20 years. (Thigpen et al., 1993) Resistance to anti-cancer drugs remains a serious obstacle for improving the prognosis of patients with ovarian cancer. A new approach for the treatment is necessary to improve the prognosis of patients with chemo-resistant ovarian cancer. Several mechanisms of drug resistance have been proposed, including a decrease in the accumulation of the drug, an increase in cellular detoxification of the drug, and an increase in DNA repair activity. (Andrew et al., 1988; Fujiwara et al., 1990; Kasahara et al., 1991; Masuda et al., 1988; Minagawa et al., 1994) Recent findings have shown that several genes are involved in control of chemo-resistance including the p53 gene. (Bichat et al., 1998; Ding et al., 1998; 1998; Kigawa et al., 1998; Lowe et al., 1994; Wang et al., 1995) and that gene therapy may be a potential strategy for the therapy of chemoresistant ovarian cancer. (Barnes et al., 1997; Kanamori et al., 1998) Ovarian cancer frequently develops widespread intraperitoneal dissemination and multi-organ involvement within the peritoneal cavity. This disease may be an appropriate target for gene therapy, because of easy access to cancer cells in abdominal cavity. Several types of gene therapy for ovarian cancer such as suicide gene and tumor suppressor gene have been reported. (Kanamori et al., 1998; Kaye, 1996; Tong et al., 1997) In this chapter, gene therapy with adenovirus-vector of a p53 gene for ovarian cancer is discussed. Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic / Plenum Publishers, New York, 2000.
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2. OVARIAN CANCER AND p53 GENE The p53 gene encodes a cell-cycle checkpoint protein that functions in the G1 phase of the cell cycle and has a pivotal role in inducing apoptosis. (Kellen, 1994) The p53 protein is a transcriptional regulator of cellular response to DNA damage. (Williams et al., 1993) Several studies have shown the critical role of the p53 gene in executing cell death in response to cytotoxic drugs, and that the mutations in the pS3 gene have been associated with the lack of response to these agents. (Kastan et al., 1995; Man et al., 1995) Changes in Bcl-2-Bax expression balance regulates p53-dependent
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