GLUCOCORTICOIDS & VITAMIN D: ROLE IN ANTI-TUMOR EFFECTS

我们实验室的研究表明，维生素D或1,25-二羟基胆骨化醇（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阻滞，调节p27/p21表达，诱导PARP裂解，提高bax/bcl-2比值，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，而同等剂量的甲基泼地酮（mp）则没有。dex和mp均能增强VDR蛋白的表达；然而，骨化三醇加指数导致类视黄醇X受体(RXR) α水平升高，骨化三醇/mp降低RXR α。骨化三醇/磷酸二醇对丝裂原活化蛋白激酶（MAPK）活性有抑制作用，而骨化三醇/磷酸二醇对MAPK活性无抑制作用。在一项口服骨化三醇和dex治疗激素难治性前列腺癌的II期临床试验中，我们观察到31%无高钙血症的患者前列腺特异性抗原（PSA）降低50%，外周血单核细胞VDR调节。我们拟从以下几个方面确定骨化三醇与dex/mp相互作用的机制：1)通过检查糖皮质激素与糖皮质激素受体（GR）结合的作用来确定糖皮质激素对肿瘤细胞的作用机制；b) RXR的差异作用；c)糖皮质激素的作用是否需要骨化三醇与VDR结合，调节与VDRE的结合，和/或肿瘤模型系统，通过确定：a)对受体（VDR/GR）和非受体（MAPK）介导的活性的影响，以及b) RXR的作用；3)通过I期临床试验评估口服骨化三醇和骨化三醇对激素难治性前列腺癌的治疗效果，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；4)骨化三醇和骨化三醇/骨化三醇对外周血单核细胞VDR、RXR和MAPK活性的调节。

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.