VITAMIN D ANALOGS AS ADJUVANTS IN CHEMOTHERAPY

治疗药物在治疗淋巴癌方面日益有效 白血病，但药物可导致髓系和粒单核细胞类型的缓解 这种疾病的复发和死亡是随之而来的。我们建议 在模型系统中研究区分试剂的潜力， 维生素D3及其类似物，作为细胞毒治疗的辅助药物 阿糖胞嘧啶(Ara C)。这项研究将在组织培养上进行 从白血病患者和正常志愿者新鲜分离的细胞。 药物细胞毒性增强机制的研究进展 维生素D将在易受这种疗法影响的白血病细胞中进行研究。 首先，我们将确定维生素D3是否会增加药物滞留。如果，当我们 预计，这种行动模式并不能完全解释观察到的 ，我们将启动一项系统的研究，研究分子变化对 白血病细胞DNA的合成、修复和表达 阿糖胞苷和维生素D3类似物的序贯治疗。这些过程 将在完整细胞和亚细胞系统中进行研究，以及 将探索癌基因的表达与细胞抑制有关 细胞的增殖、终末分化和细胞毒作用 这些基因的表达。这些知识将被用来提出新的 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.