VITAMIN D ANALOGS AS ADJUVANTS IN CHEMOTHERAPY

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Therapeutic drugs are increasingly effective in the treatment of lymphatic leukemias, but drug induced remissions of myeloid and myelomonocytic forms of this disease are followed by relapses and death. We propose to investigate in a model system the potential of differentiating agents, vitamin D3 and its analogs, as adjuncts to the cytotoxic treatment with arabinocytosine (Ara C). This study will be conducted in tissue culture on cells freshly isolated from leukemic patients, and from normal volunteers. The mechanisms responsible for the potentiation of drug cytotoxicity by vitamin D will be studied in leukemic cells susceptible to this regimen. First we will determine if vitamin D3 increases drug retention. If, as we anticipate, this mode of action does not fully account for the observed effects, we shall initiate a systematic study of molecular changes affecting the synthesis, repair and expression of DNA in leukemic cells subjected to sequential treatment with Ara C and vitamin D3 analogs. These processes will be studied both in intact cells and in subcellular systems, and oncogene expression will be explored in order to relate inhibition of cell proliferation, terminal differentiation and cytotoxicity to the altered expression of these genes. This knowledge will be utilized to propose new therapeutic strategies for improved treatment of leukemia.