The starting point in our analysis for this revised renewal application of our NCCP grant is that the disease of leukemia represents a form of cancer in which an inappropriate block to stern cell differentiation exists, coupled with an enhancement of cell proliferation. Thus, induction of differentiation might afford a method to modify biologically the malignancy by inducing the neoplastic cells to differentiate to functionally mature, post-mitotic cells. The hormonally active form of vitamin D, namely 1,25(OH)2D3, is known to be a potent inducer of differentiation via interaction with receptors in target cells. However, 1,25(OH)2D3 has been shown to have a serious dose-limiting toxicity of hypercalcemia. A fundamental premise of this application is that analogs of 1,25(OH)2D3 can be synthesized which will display selective biological responses, i.e., promote differentiation without hypercalcemia. In our first 5-year interval, we have synthesized two families of new vitamin D analogs, the arocalciferols which meet our objective criteria and the 22,23-dienes which are currently undergoing evaluation. Additionally, one other analog 1,25(OH)2 16ene-23yne-D3, has been found to be 40-fold more potent than 1,25(OH)2D3 in promoting cell differentiation with only 1.7% of the intestinal Ca2+ absorption activity. Thus, the primary overall goal of this renewal application for our NCCP proposal is to continue to synthesize, evaluate and identify new analogs of vitamin D which induce differentiation and inhibit proliferation of leukemia an preleukemia cells without causing hypercalcemia. This revised renewal application presents three interrelated projects with the following objectives: (a) to carry out a molecular mechanics computational analysis and then chemical synthesis of analogs of 1,25(OH)2D3 with conformationally restricted side-chains; (b) to carry out a vitamin D analog screening strategy which will permit an economical yet scientifically justifiable profiling of the biological properties (both beneficial and adverse) of an analog; and (c) to carry out a biological evaluation of the cell differentiating and anti-leukemic properties of the new analogs and, when attractive new target analogs are identified, to plan a clinical trial phase (1/2) to evaluate safety and efficacy in preleukemia (myelodysplastic syndrome: MDS). Note: no clinical trial will be carried out until at least the second year of the grant perio
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