ANTITUMOR MECHANISMS & THERAPEUTIC EFFECTS OF VITAMIN D

抗肿瘤机制

• 批准号: 6512877
• 负责人: CANDACE S JOHNSON
• 金额: $ 24.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6512877
• 关键词: 1,25 dihydroxycholecalciferol; T lymphocyte; analog; antineoplastics; athymic mouse; cell differentiation; cis platinum compound; combination cancer therapy; disease /disorder model; dosage; human subject; human therapy evaluation; injection /infusion; laboratory mouse; macrophage; neoplasm /cancer chemotherapy; neoplasm /cancer immunology; neoplasm /cancer pharmacology; neoplastic cell; pharmacokinetics; receptor expression; vitamin D; vitamin D receptors; vitamin therapy

DESCRIPTION: Vitamin D or 1,25-dihydroxycholecalciferol (1,25D3) inhibits proliferation, induces differentiation and modulates cell cycle control in a variety of normal and malignant cells. The applicants have demonstrated over the previous funding period that 1,25D3 or its analogs have significant anti-proliferative activity, arrest cells in G0/G1, induce expression of p27 and p21, induce PARP cleavage and enhance the anti-tumor activity of conventional chemotherapeutic agents. Dexamethasone (dex) enhances 1,25D3-mediated anti-proliferative effects and decreases 1,25D3 induced hypercalcemia: these activities may be mediated by effects on the VDr. In addition, they have completed a phase I trial with sc calcitriol in which they determined the MTD and calcitriol pharmacokinetics. The applicants propose to examine effects of 1,25D3 by the following specific aims 1) To examine the anti-tumor activity and the mechanisms involved with 1,25D3 in combination with carboplatin and/or paclitaxel by determining a) the optimum schedule- and time-dependent parameters, b) the role of apoptosis and intracellular Ca2+ changes for these effects, c) the role of cell cycle arrest, and d) the toxicities, MTD and carboplatin pharmacokinetics of calcitriol administered sc for 3 days before and after carboplatin in patients with advance solid tumors; 2) To examine the mechanisms involved in 1,25D3- mediated cell cycle arrest through a) effects on cell cycle check points, b) the role of p21 and p27, and c) the effect of calcitriol on cell cycle status, apoptosis, and VDR expression in prostate cancer patients treated with calcitriol prior to prostatectomy; and 3) To determine the role of glucocorticoids in 1,25D3-mediated activities by a) examining the effect of dex on enhanced anti-proliferative activity, b) on the down-modulation of VDR in the intestinal mucosa, and c) the effect of prednisone in combination with sc calcitriol on toxicity, the MTD and calcitriol pharmacokinetics in patients with advanced tumors.

描述：维生素 D 或 1,25-二羟基胆钙化醇 (1,25D3) 抑制 增殖、诱导分化并调节细胞周期控制 各种正常细胞和恶性细胞。 申请人已证明 在上一个资助期间，1,25D3 或其类似物具有显着的 抗增殖活性，将细胞阻滞在 G0/G1 期，诱导 p27 表达 和 p21，诱导 PARP 裂解并增强抗肿瘤活性 常规化疗药物。 地塞米松 (dex) 增强 1,25D3 介导的抗增殖作用并减少 1,25D3 诱导的增殖作用 高钙血症：这些活动可能是通过对 VDr 的影响介导的。 在 此外，他们还完成了 SC 骨化三醇的 I 期试验，其中 他们确定了 MTD 和骨化三醇药代动力学。 申请人 建议通过以下具体目标来检验 1,25D3 的影响 1) 检查 1,25D3 的抗肿瘤活性及其机制 通过确定a)最佳与卡铂和/或紫杉醇组合 时间表和时间依赖性参数，b）细胞凋亡的作用和 细胞内 Ca2+ 因这些效应而变化，c) 细胞周期的作用 逮捕，以及 d) 的毒性、MTD 和卡铂药代动力学 在卡铂治疗前后皮下注射骨化三醇 3 天 晚期实体瘤患者； 2）检查涉及的机制 1,25D3-通过 a) 对细胞周期检查的影响介导细胞周期停滞 点，b) p21 和 p27 的作用，以及 c) 骨化三醇对细胞的影响 前列腺癌患者的周期状态、细胞凋亡和 VDR 表达 前列腺切除术前用骨化三醇治疗； 3）确定角色 糖皮质激素在 1,25D3 介导的活性中的作用，通过 a) 检查效果 dex 增强抗增殖活性，b) 下调 VDR在肠粘膜中的作用，以及c)联合泼尼松的作用 SC 骨化三醇对毒性、MTD 和骨化三醇药代动力学的影响 晚期肿瘤患者。