VITAMIN D ANALOGS AS ADJUVANTS IN CHEMOTHERAPY

治疗药物在治疗慢性前列腺癌方面日益有效 淋巴细胞白血病，但药物诱导的髓系白血病和 骨髓单核细胞形式的这种疾病之后会复发和死亡。 建议扩大对……潜力的调查。 分化试剂，维生素D3及其类似物，作为 阿糖胞嘧啶(Ara-C)对白血病的细胞毒治疗本研究 在已建立的细胞系上进行体外实验，它们的变异体对 对Ara-C和分化剂，以及对新鲜分离的细胞 白血病患者或正常志愿者。的类似物的作用 维生素D在信号通路中的各种中间步骤 将对分化和停止增殖进行检查。这将是 包括即刻早期基因、蛋白激酶C的表达 蛋白质的活性、磷酸化/去磷酸化、DNA结合 转录因子和组蛋白合成的控制组蛋白。其次， 阿糖胞苷增强阿糖胞苷细胞毒性的机制 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。 我们将确定辨证论治的潜在用处 最近出现的维生素D的类似物，有 比以前研究的化合物具有更低的钙动员性能。 这将包括对白血病细胞分子变化的系统研究。 接受Ara-C和维生素D类似物的序贯治疗。 抑制细胞增殖、终末分化和细胞毒性 将与原癌基因和其他基因表达的改变有关 调控基因。第三，最近发现的HL60的交叉耐药性 对Ara-C耐药的细胞对维生素D类似物和侧支敏感性 到依托泊苷，将被研究与动员有关 细胞内钙离子和程序性细胞死亡。这一知识将是 用来提出新的治疗策略，以改进治疗 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.