The goal of this research proposal is to test the hypothesis that a newly invented class of non-calcemic vitamin D compounds, the 19-nor analogs, can inhibit growth, induce regression, and prevent metastasis of retinoblastoma (RB) with minimal toxicity. Previous preclinical studies of the other vitamin D analogs showed impressive anti-neoplastic activity, but with a level of hypercalcemic toxicity that was excessive for clinical use. Two representative 19-nor compounds which showed the greatest effectiveness in preliminary studies, 2MbisP and 2MP, will be tested using in vitro and in vivo models of RB . In RB, the most frequent primary ocular tumor of childhood, survivors of the inherited type have a substantially increased risk of second primary tumors. The principal mechanism of action of vitamin D analogs (i.e. apoptosis) is distinct from the mechanism of action of standard chemotherapy and unlike standard chemotherapy is not mutagenic, and is derived from increased expression of p53 and p21. This proposal is for a final group of well-defined experiments necessary to bring this drug to clinical trial. Specifically, the effectiveness of 2 representative 19-nor analogs will be tested on large tumors and in long term treatment. The efficacy of the drug administered subconjunctivally will be ascertained. Lastly the potency of the 19-nor compounds wil be compared to standard chemotherapy and their possible synergistic effect in multi-drug treatment established.
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