Glucocorticoids & Vitamin D: Role In Anti-Tumor Effects

说明(申请人提供)：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G0/G1期停滞，调节p27和p21，诱导caspase3、MEK和PARP裂解，抑制P-Akt，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的体外和体内抗肿瘤效果。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。在大剂量口服骨化三醇和地塞米松治疗雄激素非依赖性前列腺癌(AIPC)的II期试验中，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/地塞米松抗肿瘤作用也在前列腺癌切除或放疗后PSA升高的局限性疾病的男性中观察到。从一些试验的药代动力学(PK)数据来看，增加口服骨化三醇剂量并没有导致更高的血清骨化三醇水平；这表明生物利用度可能会降低。在前列腺癌PC-3模型中，骨化三醇分解代谢酶--细胞色素P24的抑制剂酮康唑与骨化三醇和地塞米松在体内外均有协同作用，可通过降低细胞色素P24水平而增强抗肿瘤作用。因此，糖皮质激素对骨化三醇介导的效应有不同的调节和增强作用，具有重要的治疗意义。因此，我们建议通过以下具体目标从临床和临床前研究骨化三醇联合糖皮质激素的潜在疗效和机制：1)在骨化三醇/地塞米松/酮康唑肿瘤模型的体内外确定骨化三醇信号通路中分子事件的调节；2)通过两阶段I期临床试验，评估每周递增单次静脉注射骨化三醇联合持续低剂量(200 Mg TID)或大剂量(400 Mg TID)酮康唑+地塞米松(0.5 mg QD)治疗晚期癌症的疗效和机制；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；4)在II期试验中观察每周一次静脉注射骨化三醇(剂量将从正在进行的I期试验中确定)和地塞米松(4 mg，qdx4)联合治疗男性雄激素非依赖性前列腺癌前一个月的效果。

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.