GLUCOCORTICOIDS & VITAMIN D: ROLE IN ANTI-TUMOR EFFECTS

本实验室的研究表明维生素D或1，25-二羟基胆钙化醇（骨化三醇）在体内和体外均具有显著的抗增殖活性。骨化三醇诱导G 0/G1期阻滞，调节p27/p21的表达，诱导PARP裂解，增加bax/bcl-2比率，并增强顺铂、卡铂和紫杉醇的抗肿瘤活性。地塞米松（dex）在体外和体内增强骨化三醇介导的抗肿瘤活性和维生素D受体（VDR）配体结合，而等效剂量的甲基泼尼松龙（mp）则不能。dex和mp均增强VDR蛋白表达;然而，骨化三醇加dex导致类维生素A X受体（RXR）α水平增加，骨化三醇/mp降低RXR α。骨化三醇/dex抑制丝裂原活化蛋白激酶（MAPK）活性，而骨化三醇/mp无此作用。在激素难治性前列腺癌的II期临床试验中，口服骨化三醇和dex，我们观察到31%的患者前列腺特异性抗原（PSA）降低50%，无高钙血症，外周血单核细胞的VDR调节。我们提出通过以下具体目标来确定骨化三醇和dex/mp相互作用的机制：1）通过检查以下来确定糖皮质激素对肿瘤细胞作用的机制：a）类固醇与糖皮质激素受体（GR）结合的作用; B）RXR的差异作用;和c）糖皮质激素作用是否需要骨化三醇与VDR结合、调节与VDRE和/或肿瘤模型系统的结合，通过确定：a）对受体（VDR/GR）和非受体（MAPK）介导的活性的影响，和B）RXR的作用;和3）通过进行I期试验来评估口服骨化三醇和dex在激素难治性前列腺癌中的作用，以确定：a）最大耐受剂量（MTD）、毒性和骨化三醇药代动力学，B）临床和PSA反应，和4）外周血单核细胞VDR的调节，骨化三醇和骨化三醇/dex的RXR和MAPK活性。

Studies in our laboratory demonstrate that vitamin D or 1,25- dihy6droxycholecalciferol (calcitriol) has significant anti proliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates expression of p27/p21, induces PARP cleavage, increases the bax/bcl-2 ratio and enhances the anti-tumor activity of cisplatin, carboplatin and paclitaxel. Dexamethasone (dex) potentiates calcitriol-mediated anti- tumor activity and vitamin D receptor (VDR) ligand binding in vitro and in vivo whereas equivalent doses of methylpredinsolone (mp) do not. Both dex and mp enhance VDR protein expression; however, calcitriol plus dex results in an increase in retinoid X receptor (RXR) alpha levels and calcitriol/mp decreases RXRalpha. Calcitriol/dex suppresses activity mitogen-activated protein kinase ( MAPK) activity while calcitriol/mp have no effect. In a phase II clinical trial of hormone refractory prostate cancer with oral calcitriol and dex, we observed a 50% reduction in prostate specific antigen (PSA) in 31% of patients with no hypercalcemia and a modulation of VDR from peripheral blood monocytes. We propose to determine the mechanisms of calcitriol and dex/mp interaction by the following specific aims: 1) To determine the mechanisms involved in glucocorticoid effects on tumor cells by examining: a) the role of steroid binding to the glucocorticoid receptor (GR); b) the differential role of RXR; and c) whether glucocorticoid effects require calcitriol binding to the VDR, modulate binding to the VDRE, and/or tumor model systems by determining: a) the effect on receptor (VDR/GR) and non-receptor (MAPK) mediated activities, and b) the role of RXR; and 3) To evaluate oral calcitriol and dex in hormone refractory prostate cancer through conduct of a phase I trial to determine: a) the maximum tolerated dose (MTD), toxicities and calcitriol pharmacokinetics, b) the clinical and PSA response, and 4) modulation of peripheral blood monocyte VDR, RXR and MAPK activity by calcitriol and calcitriol/dex.