VITAMIN D ANALOGS AS ADJUVANTS IN CHEMOTHERAPY

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DESCRIPTION: (Adapted from the applicant's description). This application proposes to investigate analogs of vitamin D3, (1,25D3) in combinations with antileukemia agents such as arabinocytosine or etoposide and related compounds. The cellular responses to D3 analogs and drug combinations will be monitored for changes in the cell cycle traverse and the expression of genes which control this traverse by transduction of signals for growth, differentiation, and programmed cell death. The genes studied will include those encoding the regulatory subunits of cell cycle dependent protein kinase complexes, i.e., cyclins D, E, A, and B, and inhibitors of this activity, proteins p16 and p21. Transduction of signals initiated by these analogs will also be assessed by determinations of intracellular calcium, by changes in the expression and activity of calcium, phospholipid-activated protein kinase C, and by evaluation of the ability of PKC to increase the activity and upregulated the expression of the plasma membrane calcium pump. These approaches are intended to increase the understanding of the cellular actions of VD3 analogs, and to provide a basis for better design of clinical trails now being initiated.