VITAMIN D ANALOGS AS ADJUVANTS IN CHEMOTHERAPY

治疗药物在治疗 淋巴细胞白血病，但药物诱导的缓解骨髓和 这种疾病的骨髓单核细胞形式之后是复发和死亡。 建议扩大对以下方面潜力的调查： 分化剂，维生素D3及其类似物， 用阿糖胞苷（Ara-C）进行白血病的细胞毒性治疗。 本研究 在体外对已建立的细胞系进行，其变体具有抗性 Ara-C和分化剂，并对新鲜分离的细胞， 白血病患者或正常志愿者。 类似物的作用 维生素D对信号通路中的各种中间步骤的影响 将检查分化和增殖的停止。 这将 包括即刻早期基因蛋白激酶C 活性，蛋白质的磷酸化/去磷酸化， 转录因子和组蛋白合成的控制。 二是 Ara-C细胞毒性增强的机制 维生素D将在对该方案敏感的白血病细胞中进行研究。 我们将确定分化治疗的潜在用途， 维生素D的类似物，最近已经变得可用，并已 比先前研究的化合物更低的钙动员性能。 这将包括白血病细胞分子变化的系统研究 用Ara-C和维生素D类似物进行顺序处理。 抑制细胞增殖、终末分化和细胞毒性 将与原癌基因和其他 调节基因 第三，最近发现的HL 60交叉耐药性 对阿糖胞苷和维生素D类似物耐药的细胞， 依托泊苷，将研究有关动员 细胞内钙和程序性细胞死亡。 这些知识将 用于提出新的治疗策略，以改善治疗 白血病

Therapeutic drugs are increasingly effective in the treatment of lymphocytic leukemias, but drug induced remissions of myeloid and myelomonocytic forms of this disease are followed by relapses and death. It is proposed to extend the investigation of the potential of differentiating agents, vitamin D3 and its analogs, as adjuncts to the cytotoxic treatment of leukemia with arabinocytosine (Ara-C). This study is conducted in vitro on established cell lines, their variants resistant to Ara-C and differentiation agents, and on cells freshly isolated from leukemic patients or from normal volunteers. The action of the analogs of vitamin D on the various intermediate steps in the pathways that signal differentiation and cessation of proliferation will be examined. This will include the expression of the immediate-early genes, protein kinase C activity, phosphorylation/dephosphorylation of proteins, the DNA binding of transcription factors, and control of histone synthesis. Secondly, the mechanisms responsible for the potentiation of Ara-C cytotoxicity by vitamin D will be studied in leukemic cells susceptible to this regimen. We will determine the potential usefulness of differentiation therapy of the analogs of vitamin D which recently have become available, and have lower calcium mobilizing properties than the previously studied compounds. This will include a systematic study of molecular changes in leukemic cells subjected to sequential treatments with Ara-C and vitamin D analogs. Inhibition of cell proliferation, terminal differentiation and cytotoxicity will be related to the altered expression of proto-oncogenes and other regulatory genes. Third, the recently discovered cross-resistance of HL60 cells resistant to Ara-C to vitamin D analogs, and collateral sensitivity to etoposide, will be studied in relation to the mobilization of intracellular calcium and programmed cell death. This knowledge will be utilized to propose new therapeutic strategies for improved treatment of leukemia.