VITAMIN D ANALOGS AS ADJUVANTS IN CHEMOTHERAPY

维生素 D 类似物作为化疗佐剂

• 批准号: 2091572
• 负责人: George P Studzinski
• 金额: $ 13万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-06-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091572
• 关键词: cell differentiation; cytosine arabinoside; cytotoxicity; drug resistance; histones; human subject; lymphocytic leukemia; neoplasm /cancer nutrition therapy; nutrition related tag; phosphorylation; protein kinase C; tissue /cell culture; vitamin D; vitamin analog; vitamin therapy

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.

治疗药物在治疗中越来越有效 淋巴细胞白血病，但药物诱导的髓系和白血病缓解 这种疾病的骨髓单核细胞形式随后会复发和死亡。 建议扩大对潜力的调查 分化剂、维生素 D3 及其类似物，作为辅助剂 用阿拉伯胞嘧啶（Ara-C）对白血病进行细胞毒治疗。 这项研究 在体外对已建立的细胞系进行，其变异体具有抗性 Ara-C 和分化剂，以及新鲜分离的细胞 白血病患者或正常志愿者。 类似物的作用 维生素 D 对信号通路中各个中间步骤的影响 将检查分化和增殖停止。 这将 包括立即早期基因、蛋白激酶 C 的表达 活性、蛋白质的磷酸化/去磷酸化、DNA 结合 转录因子和组蛋白合成的控制。 其次， Ara-C 细胞毒性增强的机制 将在对该方案敏感的白血病细胞中研究维生素 D。 我们将确定分化疗法的潜在用途 最近已上市的维生素 D 类似物 与之前研究的化合物相比，钙动员特性较低。 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 类似物的连续治疗。 抑制细胞增殖、终末分化和细胞毒性 与原癌基因和其他基因表达的改变有关 调控基因。 三、最近发现的HL60交叉耐药性 细胞对 Ara-C 和维生素 D 类似物具有抗性，以及附带敏感性 依托泊苷，将研究与动员的关系 细胞内钙和程序性细胞死亡。 这些知识将会 用于提出新的治疗策略以改善治疗 白血病。