Mda-7, A Novel Melanoma Differentiation Associated Gene with Promise for Cancer Gene Therapy
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Mda-7, A NOVEL MELANOMA DIFFERENTIATION ASSOCIATED GENE WITH PROMISE FOR CANCER GENE THERAPY Malavi T. Madireddi1, Zao-Zhong Su1, Charles S. H. Young4 Neil I. Goldstein5, and Paul B. Fisher1,2,3 Departments of Urology1 Pathology2, Neurosurgery3 and Microbiology4 Herbert Irving Comprehensive Cancer Center Columbia University College of Physicians and Surgeons New York, New York, 10032 and GenQuest Incorporated5 New York, New York, 10032
1. GENERAL INTRODUCTION The carcinogenic process is multistep in terms of its etiology and multifactor with respect to its development (Fisher, 1984; Bishop, 1991; Vogelstein and Kinzler, 1991; Knudson, 1993; Du et al., 1998; Kieff, 1998). Tumor cells often contain multiple genetic abnormalities, including inactivation of tumor suppressor genes, activation of oncogenes and changes in the expression of cell cycle regulatory genes, DNA damage and repair genes and genes that can directly promote cancer aggressiveness (Fisher, 1984; Bishop, 1991; Vogelstein and Kinzler, 1991; Knudson, 1993; Levine, 1993; Hartwell and Kastan, 1994; Su et al., 1997). The ability of a single tumor suppressor gene, such as p53, to reverse the cancerous properties of human tumors with multiple genetic abnormalities in vitro and in vivo in human tumor xenograft models has provided the impetus for defining strategies for the gene-based therapy of human cancer (Crystal, 1995; Xu et al., 1996; Roth and Cristiano, 1997; Anderson et al., 1998; Chen and Mixson, 1998; Hwang et al., 1998; Roth et al., 1998; Takeda et al., 1998). The observation that a number of genetic mutations can result in neoplastic transformation has led many investigators to speculate that gene therapy could become a useful modality to treat cancer (Fisher, 1984; Levine, 1993; Crystal, 1995; Takeda et al., 1998). Conceptually, gene replacement therapy appears to be a reasonable and viable approach to treat neoplastic diseases; by restoring more normal gene expression patterns with regards to tumor suppressor gene function within the tumor cell it may be possible Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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to revert the transformed phenotype to a more normal state. However, for this approach to be realized it will be necessary to develop improved delivery systems, both viral and non-viral, and to identify suppressor genes that selectively target cancer cells for growth arrest and apoptosis while sparing normal cells and tissues from damage. Since tumor cells undergo a number of genetic changes in addition to the loss of function of tumor suppressors, the ultimate objective of cancer gene-therapy should not simply be restoration of function of the specific lost tumor suppressor. Instead, it is more important to reestablish growth control to an extent that would singly or in combination with additional tumor suppressors or chemotherapeutic agents lead to selective tumor cell growth suppression and apoptosis. To date, a number of
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