ANTITUMOR MECHANISMS & THERAPEUTIC EFFECTS OF VITAMIN D

抗肿瘤机制

• 批准号: 2414384
• 负责人: CANDACE S JOHNSON
• 金额: $ 24.42万
• 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 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414384
• 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

The active metabolite of vitamin D, l,25(OH)2D or calcitriol, is most widely known for its role in regulation of bone and mineral metabolism. Vitamin D, however, has also been shown to modulate cell growth and differentiation of several normal and malignant cell types. In vitro, vitamin D inhibits cell proliferation and in vivo, prolongs survival and inhibits tumor growth in a variety of murine leukemia/tumor and human xenograft tumor model systems. Clinical efforts, however, have been hampered due to hypercalcemia, the dose limiting toxicity. As a result, vitamin D analogues such as l,25(OH)2-16-ene-23-yne-D, have been developed that maintain anti-tumor activity without inducing hypercalcemia. We have demonstrated here that both vitamin D parent (calcitriol) and the analogue had significant anti-tumor activity in vitro and in vivo. At high doses, the parent induced tumor inhibition with severe hypercalcemia whereas, the analogue resulted in an increase in tumor growth inhibition without significant hypercalcemia. In addition, significant enhancement of anti- tumor activity was observed when vitamin D was combined with either glucocorticoids or cisplatin. Therefore, we propose to examine the anti- tumor mechanisms and therapeutic efficacy of vitamin D parent or analogue in animal tumor models and to determine whether they can be exploited for clinical use. The aims of this study include: l) To characterize and compare the anti- tumor response of the vitamin D parent and analogue using murine tumor model systems; 2) To determine whether relationships exist between vitamin D receptor expression in vivo, state of differentiation and/or therapeutic efficacy with vitamin D parent or analogue and can these activities be enhanced when combined with glucocorticoids; 3) To examine the anti-tumor activity of vitamin D parent or analogue when administered in combination with cisplatin; and 4) To determine in the phase I setting the maximum tolerated dose and pharmacokinetics of vitamin D parent (Calcijex) by subcutaneous injection in patients with advanced solid tumors with and without steroid therapy.

维生素 D、l,25(OH)2D 或骨化三醇的活性代谢物是最重要的 因其在骨和矿物质代谢调节中的作用而广为人知。 然而，维生素 D 也被证明可以调节细胞生长和 几种正常和恶性细胞类型的分化。 体外， 维生素 D 在体内抑制细胞增殖，延长生存期 抑制多种小鼠白血病/肿瘤和人类的肿瘤生长 异种移植肿瘤模型系统。 然而，临床努力已 由于高钙血症阻碍了剂量限制性毒性。 因此， 已开发出维生素 D 类似物，例如 l,25(OH)2-16-ene-23-yne-D 维持抗肿瘤活性而不诱发高钙血症。 我们有 此处证明维生素 D 母体（骨化三醇）和类似物 具有显着的体外和体内抗肿瘤活性。 在高剂量下， 亲本诱导肿瘤抑制并伴有严重高钙血症，而 类似物导致肿瘤生长抑制增加，而无需 明显的高钙血症。 此外，显着增强抗 当维生素 D 与任一药物联合使用时，观察到肿瘤活性 糖皮质激素或顺铂。 因此，我们建议研究反 维生素D母体或类似物的肿瘤机制和治疗功效 动物肿瘤模型并确定它们是否可以用于 临床使用。 本研究的目的包括： l) 表征和比较反 使用小鼠肿瘤观察维生素 D 母体和类似物的肿瘤反应 模型系统； 2) 确定维生素之间是否存在关系 D 受体体内表达、分化状态和/或治疗 维生素 D 母体或类似物的功效，这些活性可以 与糖皮质激素合用时效果增强； 3）检查抗肿瘤作用 联合给药时维生素 D 母体或类似物的活性 与顺铂； 4) 确定第一阶段设置的最大值 维生素 D 母体 (Calcijex) 的耐受剂量和药代动力学 晚期实体瘤患者皮下注射 无需类固醇治疗。