Abnormalities in differentiation an growth control occur frequently in human cancers. Treatment of human melanoma cells with the combination of recombinant human fibroblast interferon and the protein kinase C activating, anti-leukemic compound mezerein brings about a loss of tumorigenic potential that correlates with an irreversible suppression in growth and the induction of terminal differentiation. it is hypothesized that this process correlates with differential expression of genes directly regulating cancer cell growth and differentiation. By means of subtraction hybridization, a gene associated with induction of irreversible growth arrest, cancer reversion and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7), has been identified. Ectopic expression of mda-7 using a recombinant adenovirus, Ad.mda-7 S, results in growth suppression and apoptosis in diverse cancer cell types, including tumor cells with wild-type p53 or mutant for p53, Rb or p53 + Rb. Additionally, Ad.mda-7 S inhibits the growth and progression of human breast and cervical cancer cells in vivo in nude mice. In contrast to its effect on cancer cells, mda-7 displays no apparent negative effect on growth or survival in normal human skin fibroblast or mammary epithelial cells. in this context, mda-7 may prove useful for selectively targeting human cancer cells for eradication. The present studies will test this hypothesis and evaluate the effect of mda-7 expression on growth, tumorigenicity and metastatic potential of human melanoma cells. Two strategies for expressing mda7 in metastatic C8161 human melanoma cells will be used. One will involve viral-mediated ectopic expression of mda-7, via Ad.mda-7 S, and the second approach will use stable melanoma cell lines containing a tetracycline inducible mda-7 gene. To evaluate potential effects on normal melanocytes we will use Ad.mda-7 S. If mda-7 displays selective inhibitory/apoptosis inducing effects on melanoma but not in normal melanocytes, this gene could provide a novel means of therapy for human melanoma without inducing nonspecific damage to normal melanocytes and skin cells.
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