Anti-tumor activity of calcitriol: pre-clinical and clinical studies
Anti-tumor activity of calcitriol: pre-clinical and clinical studies
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DOI：
10.1016/j.jsbmb.2004.03.068
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发表时间：
2004-05-01
影响因子：
4.1
通讯作者：
Johnson, CS
中科院分区：
文献类型：
--
作者：
Trump, DL;Hershberger, PA;Johnson, CS
1，25-二羟基胆钙化醇（骨化三醇）因其对骨和矿物质代谢的作用而被广泛认可。流行病学数据表明，低维生素D水平可能在前列腺癌和其他肿瘤的发生中发挥作用。骨化三醇是一种有效的抗增殖剂在各种恶性细胞类型。在前列腺癌、乳腺癌、结直肠癌、头颈癌和肺癌以及淋巴瘤、白血病和骨髓瘤模型系统中，骨化三醇在体外和体内具有显著的抗肿瘤活性。骨化三醇的作用与G（0）/G（1）阻滞的增加、细胞凋亡和分化的诱导、生长因子受体表达的调节有关。糖皮质激素增强骨化三醇的抗肿瘤作用并降低骨化三醇诱导的高钙血症。骨化三醇增强许多细胞毒性剂的抗肿瘤作用，并抑制肿瘤细胞的运动性和侵袭性以及新血管的形成。骨化三醇单独或与卡铂、紫杉烷类或地塞米松联合治疗雄激素依赖性和非依赖性前列腺癌和晚期癌症患者的I期和II期试验已经启动。数据表明，高剂量骨化三醇是可行的间歇时间表，没有剂量限制性毒性已经遇到，最佳剂量和时间表正在划定。在雄激素非依赖性前列腺癌（AIPC）中观察到高剂量骨化三醇+地塞米松联合治疗的临床应答，在AIPC中观察到多西他赛的抗肿瘤作用明显增强。这些结果表明，高间歇剂量的骨化三醇可以无毒性地施用于患者，MTD尚未确定，并且骨化三醇具有作为抗癌剂的潜力。(C)2004爱思唯尔有限公司保留所有权利。
1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G(0)/G(1) arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glueocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol + dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent. (C) 2004 Elsevier Ltd. All rights reserved.