Pre-clinical Studies with Tumor Suppressor Genes
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PRE-CLINICAL STUDIES WITH TUMOR SUPPRESSOR GENES Prem Seth Medical Breast Cancer Section Medicine Branch Building 10, Room 12 N226 National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 Cancer progression is considered to be a multi-stage process. Several genetic and epi-genetic factors have been suggested to participate in this process. One molecular event which has been implicated in the development of many cancers is the loss of a tumor suppressor function of many genes. Therefore, it is a reasonable idea to target these defects in cancer cells, in an effort to correct these abnormalities in the cancer cells. Several tumor suppressor genes have been isolated in recent years. Although a significant amount of work has been conducted using p53 gene, in theory each one of these tumor suppressor genes can be potentially useful for cancer gene therapy. The purpose of the following section is to review our current status of the use of tumor suppressor genes and some of the future challenges we are likely to face for the successful therapeutic applications of these tumor suppressor genes.
1. p53 GENE p53 is a tumor suppressor gene that is frequently mutated in many cancers (Nigro et al., 1989). It is estimated that at least half of the human malignancies including breast, ovary, lung, colorectal carcinomas are associated with mutations in p53. It has been postulated that wild type p53 can regulate the cell growth either by controlling the cell cycle progression at G1 to S, and G2 to M phase, or by inducing apoptosis (programmed cell death) (Ko and Prives, 1996). Thus during DNA damage by a variety of genotoxic stress situations, p53 can induce cell cycle arrest, thus giving an opportunity to repair the DNA. If cells fail to repair the DNA, p53 can induce apoptosis of the potentially damaged cell. It is believed that cancer cells defective in p53 have lost this ability to undergo cell growth by cell cycle progression and apoptosis, and hence acquire the transformed phenotype. It is therefore only logical to investigate if replacing the mutant p53 by a wild type copy Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic / Plenum Publishers, New York, 2000.
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of p53 or targeting the mutant form of p53 will reverse the phenotype. Many laboratories have evaluated the effect of over-expressing p53 protein on cancer cells (Seth, 1998). This has been studied by ecotopic expression of wild type p53 using non-viral vectors, and viral vectors as described below.
Initial experiments were conducted using plasmid-mediated p53 expression. Cancer cells tranfected with a plasmid DNA and a selectable marker neomycin, exhibited a reduction in the colony number when treated with G418. Interestingly this colony number was dramatically reduced in cells with endogenous mutant p53 (Baker et al., 1990; Casey et al., 1991). In another study, a plasmid containing p53 driven by a metallothionein promoter was shown to induce apoptosis in human colon cancer cell
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