VITAMIN D ANALOGS AS ADJUVANTS IN CHEMOTHERAPY

治疗药物在治疗淋巴结转移中越来越有效。 白血病，但药物诱导的骨髓和骨髓单核细胞形式的缓解 这种疾病的复发和死亡。 我们建议 在模型系统中研究差异化代理的潜力， 维生素D3及其类似物，作为细胞毒性治疗的替代品， 阿糖胞苷（Ara C）。 本研究将在组织培养中进行， 从白血病患者和正常志愿者新鲜分离的细胞。 药物毒性增强的机制 维生素D将在对该方案敏感的白血病细胞中进行研究。 首先，我们将确定维生素D3是否会增加药物保留。 如果正如我们 预期，这种作用模式并不能完全解释所观察到的 影响，我们将启动一个分子变化的系统研究， 白血病细胞中DNA的合成、修复和表达 用阿糖胞苷C和维生素D3类似物顺序治疗。 这些过程 将在完整细胞和亚细胞系统中进行研究， 将探讨癌基因表达，以便将细胞抑制与细胞增殖和细胞凋亡联系起来。 增殖、终末分化和对改变的 这些基因的表达。 这些知识将用于提出新的 用于改善白血病治疗的治疗策略。

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.