Evaluation of CYP24 as a Target for Enhancing Vitamin D

CYP24 作为增强维生素 D 靶标的评估

• 批准号: 6934728
• 负责人: DONALD L TRUMP
• 金额: $ 33.99万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934728
• 关键词: 1,25 dihydroxycholecalciferol; apoptosis; athymic mouse; biological signal transduction; clinical research; clinical trial phase I; combination chemotherapy; cytochrome P450; dexamethasone; drug screening /evaluation; enzyme activity; genetic transcription; human subject; ketoconazole; neoplasm /cancer chemotherapy; oral administration; patient oriented research; pharmacokinetics; receptor expression; vitamin D receptors; vitamin metabolism; vitamin therapy

DESCRIPTION (provided by applicant): Vitamin D signaling pathways are important targets in cancer therapeutics. In vitro and in vivo calcitriol (1,25 dihydroxycholcalciferol) is antiproliferative and potentiates the antitumor effects of cytotoxic agents (e.g. taxanes, platinum analogues, antracenediones). High dose dexamethasone (Dex) potentiates the antitumor effects and blunts calcitriol-induced hypercalcemia. Administration of high doses of calcitriol + Dex in men with advanced and early prostate cancer as well as combination therapy with taxanes or platinum analogues is safe and clear evidence of antitumor effects have been seen. Preclinical data indicate that antitumor effects depend on high exposure to calcitriol which may be limited by: [1] apparent "saturable absorption" following oral administration, which may depend on induction of mucosal and hepatic metabolism of calcitriol by CYP24, the enzyme most active in calcitriol catabolism [2] intratumor catabolism of calcitriol by CYP24. We have shown that ketoconazole, an inhibitor of CYP24, enhances the anti-tumor effects of calcitriol and decreases CYP24 activity in preclinical models. In our clinical trials of high dose calcitriol we demonstrated induction of GYP 24 activity in peripheral blood monocytes. We hypothesize that oral administration of calcitriol + ketoconazole may facilitate higher systemic and intratumoral exposure through inhibition calcitriol oxidative catabolism. Therefore, we propose: SA1: Evaluate escalating doses of oral calcitriol QDx3, D1,2,3 weekly in combination with oral, high dose (400mg TID) ketoconazole + physiologic replacement doses of dex (0.5mg BID) in patients with advanced cancer to determine the (a) maximum tolerated dose (MTD) of oral calcitriol + ketoconazole/Dex (b) pharmacokinetics of calcitriol +/- ketoconazole/dex (c) safety and toxicity of calcitriol/ketoconazole/Dex (d) effect of ketoconazole/Dex on PBMC CYP24 levels (e) to determine modulation of VDR, a marker of calcitriol effect in PBMC before and after therapy. SA2: Determine the modulation of calcitriol signaling pathways in vitro and in vivo by examining the: a) effect of ketoconazole and more specific CYP24 inhibitors on calcitriol catabolism, vitamin D receptor expression, expression of apoptosis markers whether a relationship exists between modulation of these effects in vitro on tumor cells and a significant antitumor response in vivo in prostate, pancreatic and lung cancer models

描述（由申请人提供）：维生素D信号通路是癌症治疗剂的重要靶标。体外和体内钙化（1,25二羟基胆碱钙）是抗增殖性的，并增强了细胞毒性剂的抗肿瘤作用（例如，紫杉虫，铂，类似物，抗酸）。高剂量地塞米松（DEX）增强了抗肿瘤作用，并钝化了骨化三醇诱导的高钙血症。在患有晚期和早期前列腺癌的男性以及与紫杉烷或铂类似物的联合疗法中，高剂量的骨化三醇 + DEX给药是安全而明确的抗肿瘤作用证据。 Preclinical data indicate that antitumor effects depend on high exposure to calcitriol which may be limited by: [1] apparent "saturable absorption" following oral administration, which may depend on induction of mucosal and hepatic metabolism of calcitriol by CYP24, the enzyme most active in calcitriol catabolism [2] intratumor catabolism of calcitriol by CYP24.我们已经表明，CYP24的抑制剂Ketoconazole增强了钙三醇的抗肿瘤作用，并降低了临床前模型中CYP24活性。在我们的高剂量钙化三醇的临床试验中，我们证明了外周血单核细胞中GYP 24活性的诱导。我们假设口服骨化三醇 +酮康唑可能通过抑制骨化三醇氧化分解代谢来促进更高的全身和肿瘤内暴露。因此，我们提出：SA1：评估口服钙钙三醇QDX3，每周D1,2,3与口服，高剂量（400mg TID）酮康唑 +生理替代剂量的Dex（0.5mg BID）患者的晚期癌症患者的最大耐受性（A）最大耐受剂量（A）的剂量（A）最大剂量（A）酮康唑/DEX（B）钙三醇+/-酮康唑/DEX（C）钙甲酸/酮康唑/DEX（D）酮康唑/DEX对PBMC CYP24水平（e）对VDR效应的PBMC CYP24水平（e）对PBMC CYTIOL的调节的安全性和毒性。 SA2：通过检查：a）酮康唑和更具体的CYP24抑制剂对钙三醇分解代谢，维生素D受体表达，凋亡的表达，凋亡的表达来确定体外和体内的调节调节肺癌模型