Development of weekly high-dose calcitriol based therapy for prostate cancer
Development of weekly high-dose calcitriol based therapy for prostate cancer
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DOI：
10.1016/s1078-1439(03)00170-4
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发表时间：
2003-09-01
影响因子：
2.7
通讯作者：
Beer, TM
中科院分区：
文献类型：
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作者：
Beer, TM
骨化三醇是维生素D受体（VDR）的主要生物活性配体，已显示在前列腺癌和多种其他肿瘤的体外和体内模型中抑制癌细胞增殖。此外，骨化三醇的活性似乎是累加的，并且在一些实验系统中，与地塞米松和几种细胞毒性化疗剂协同。虽然已经证明了对细胞周期进展、诱导凋亡、抑制血管生成和降低肿瘤侵袭力的作用，但VDR介导的抗肿瘤活性的确切机制仍不完全清楚。骨化三醇的抗心律失常活性需要该化合物的基本上超生理浓度。骨化三醇每日给药的剂量递增受到可预测的高钙血症和/或高钙尿症的严重限制。间歇性给予骨化三醇克服了这一局限性。在俄勒冈州健康与科学大学，每周口服骨化三醇可以使血清骨化三醇浓度达到1 nM以上的峰值，该浓度在体外抑制前列腺癌增殖超过50%。然后，在一项针对转移性雄激素非依赖性前列腺癌男性进行的II期临床试验中，每周一次的高剂量钙三醇与每周一次的多西他赛联合使用。治疗导致81%的患者PSA缓解（定义为确认降低50%）。这种活性水平，以及11.4个月的中位进展时间和19.5个月的中位生存期，与多西他赛单药治疗的结果相比具有优势，并导致最近在同一患者人群中开展了多西他赛联合骨化三醇或安慰剂的随机试验。(C)2003年爱思唯尔公司All rights reserved.
Calcitriol, the principal biologically active ligand of the Vitamin D receptor (VDR), has been shown to inhibit cancer cell proliferation in in vitro and in vivo models of prostate cancer and a wide range of other neoplasms. In addition, calcitriol's activity appears to be additive, and in some experimental systems, synergistic with dexamethasone and several cytotoxic chemotherapy agents. While effects on progression through the cell cycle, induction of apoptosis, inhibition of angiogenesis, and reduction in tumor invasiveness have been demonstrated, the exact mechanisms of VDR-mediated antineoplastic activity remain incompletely understood. Antineoplastic activity of calcitriol requires substantially supraphysiologic concentrations of this compound. Dose escalation of calcitriol administered daily was severely limited by predictable hypercalcemia and/or hypercalcuria. This limitation has been overcome with intermittent dosing of calcitriol. At Oregon Health & Science University, weekly oral administration of calcitriol allowed the attainment of peak serum calcitriol concentrations well above 1 nM, a concentration that inhibits prostate cancer proliferation by more than 50% in vitro. Weekly high-dose calcitriol was then combined with weekly docetaxel in a Phase II clinical trial carried out in men with metastatic androgen-independent prostate cancer. Treatment resulted in PSA response (defined as a confirmed 50% reduction) in 81% of patients. This level of activity, as well as the median time to progression of 11.4 months and median survival of 19.5 months, compared favorably to results with docetaxel alone and led to the development of a recently initiated randomized trial of docetaxel with calcitriol or placebo in the same patient population. (C) 2003 Elsevier Inc. All rights reserved.