Glucocorticoids & Vitamin D: Role In Anti-Tumor Effects

糖皮质激素

• 批准号: 7636769
• 负责人: CANDACE S JOHNSON
• 金额: $ 38.27万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636769
• 关键词: 25-hydroxycholecalciferol-24-hydroxylase; Address; Advanced Malignant Neoplasm; Aftercare; Antitumor Response; Apoptosis; Apoptotic; Area Under Curve; Binding; Biological Availability; Biological Models; Calcitriol; Carboplatin; Caspase; Catabolism; Cell Line; Cell Survival; Clinical Data; Complex; Cyclin-Dependent Kinase Inhibitor; Cytotoxic agent; Data; Dexamethasone; Dihydroxycholecalciferols; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Enzymes; Event; Figs - dietary; G1 Arrest; Gene Targeting; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Homologous Gene; Human; Hypercalcemia; In Vitro; Intestinal Mucosa; Ketoconazole; Laboratories; Ligand Binding; Localized Disease; Lung; MEKKs; Maximum Tolerated Dose; Measurable Disease; Mediating; Metabolism; Minerals; Mitogen-Activated Protein Kinases; Modeling; Molecular; Multiple Myeloma; Mus; Oral; Oral Administration; Paclitaxel; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Phosphotransferases; Platinum; Progress Reports; Prostate; Prostate Squamous Cell Carcinoma; Prostate-Specific Antigen; Prostatectomy; Rattus; Reporting; Research Personnel; Role; Route; Safety; Serum; Signal Pathway; Signaling Molecule; Site; Staging; TP53 gene; Taxane Compound; Therapeutic; Toxic effect; Vitamin D; Vitamin D3 Receptor; analog; androgen independent prostate cancer; base; bone; calcium absorption; caspase-3; in vitro activity; in vivo; inhibitor/antagonist; irradiation; man; men; monocyte; neoplastic cell; peripheral blood; pre-clinical; receptor; receptor expression; response; taxane; tumor

DESCRIPTION (provided by applicant): Vitamin D, 1,25 dihydroxycholecalciferol (calcitriol) has significant antiproliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates p27 and p21, induces cleavage of caspase 3, MEK, and PARP, inhibits P-Akt and significantly increases MEKK-1 and the p53 homologue, p73. Also, calcitriol significantly enhances the in vitro and in vivo antitumor efficacy of platinum analogues and taxanes. In vitro and in vivo, dexamethasone (dex) potentiates calcitriol-mediated antitumor activity through the vitamin D receptor (VDR). In a phase II trial in androgen-independent prostate cancer (AIPC) with high dose oral calcitriol and dex, we observed a 50% reduction in serum prostate specific antigen (PSA) in 28% of patients. Calcitriol/dex antitumor effects were also noted in men with localized disease with a rising PSA following prostatectomy or irradiation. From the pharmacokinetic (pk) data from a number of trials, increasing oral doses of calcitriol did not result in higher serum calcitriol levels; suggesting a potential decrease in bioavailability. Ketoconazole, an inhibitor of CYP24, the enzyme responsible of catabolism of calcitriol, can synergize with calcitriol and dex both in vitro and in vivo in the prostate PC-3 model by enhancing antitumor effects with decreases in CYP24 levels. Therefore, glucocorticoids differentially modulate and enhance calcitriol-mediated effects and have significant therapeutic implications. Therefore, we propose to examine the potential efficacy and mechanisms of calcitriol in combination with glucocorticoids both clinically and pre-clinically by addressing the following specific aims: 1) to determine the modulation of the molecular events in the calcitriol signaling pathway in vitro and in vivo in tumor models of calcitriol/dex/ketoconazole; 2) to evaluate an escalating single dose of iv calcitriol weekly in combination with continuous low dose (200 mg TID) or high dose (400mg TID) ketoconazole + dexamethasone (0,5mg QD) in patients with advanced cancer through the conduct of a two stage, phase I clinical trial; 3) to determine the mechanisms of the glucocorticoid enhanced antitumor effect of calcitriol in vitro and in vivo and 4) to examine in a phase II trial the effect of a single dose of iv calcitriol weekly (dose to be determined from the ongoing phase I trial) and dexamethasone (4mg, QDx4) weekly for a month prior to combining with in men with androgen independent prostate cancer.

描述（由申请方提供）：维生素D，1，25二羟基胆钙化醇（骨化三醇）在体内和体外具有显著的抗增殖活性。骨化三醇诱导G 0/G1停滞，调节p27和p21，诱导半胱天冬酶3、MEK和PARP的裂解，抑制P-Akt并显著增加MEKK-1和p53同源物p73。此外，骨化三醇显著增强铂类似物和紫杉烷类的体外和体内抗肿瘤功效。在体外和体内，地塞米松（dex）通过维生素D受体（VDR）增强骨化三醇介导的抗肿瘤活性。在雄激素非依赖性前列腺癌（AIPC）的II期临床试验中，我们观察到28%的患者血清前列腺特异性抗原（PSA）降低了50%。骨化三醇/dex的抗肿瘤作用也注意到在局部疾病的男性与PSA升高后，前列腺切除术或放疗。根据多项试验的药代动力学（pk）数据，增加骨化三醇的口服剂量不会导致血清骨化三醇水平升高;这表明生物利用度可能降低。酮康唑是一种CYP 24（负责骨化三醇催化的酶）的抑制剂，在体外和体内前列腺PC-3模型中可与骨化三醇和地塞米松协同作用，通过降低CYP 24水平增强抗肿瘤作用。因此，糖皮质激素差异调节和增强骨化三醇介导的作用，并具有重要的治疗意义。因此，我们建议通过以下具体目的来研究骨化三醇与糖皮质激素组合在临床和临床前的潜在功效和机制：1）在骨化三醇/地塞米松/酮康唑的肿瘤模型中，在体外和体内确定骨化三醇信号通路中的分子事件的调节; 2）评价每周递增单剂量iv骨化三醇与连续低剂量（200 mg TID）或高剂量（400 mg TID）酮康唑+地塞米松（0，5 mg QD）在晚期癌症患者中通过进行两个阶段的I期临床试验; 3）确定糖皮质激素增强骨化三醇体外和体内抗肿瘤作用的机制，以及4）在II期试验中检查每周静脉注射单剂量骨化三醇的效果（剂量由正在进行的I期试验确定）和地塞米松（4 mg，QDx 4）每周一次，持续一个月，然后与雄激素非依赖性前列腺癌男性联合。