Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy.
Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy.
复制标题
DOI：
10.1097/ppo.0b013e3181c51ee6
复制
发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Johnson CS
中科院分区：
文献类型：
--
作者：
Trump DL;Deeb KK;Johnson CS
大量的临床前和流行病学数据表明，维生素D可能在癌症的发病机制、进展和治疗中发挥作用。许多流行病学研究支持这一假设，即血清维生素D水平较低的个体患多种癌症的风险较高。这些研究中维生素D水平的测量包括维生素D水平的替代估计值（居住在北方纬度、活动史和阳光照射）以及测量的血清25（OH）胆钙化醇水平。也许这些流行病学研究中最强有力的是Giovannucci及其同事的研究，他们开发并验证了血清25（OH）胆钙化醇水平的估计值，并报告说，在卫生专业人员研究中的40，000多名个体中，25（OH）胆钙化醇水平增加62.5ng/mL与头颈部，食道，胰腺癌和急性白血病减少> 50%。不幸的是，非常有限的数据可以表明是否给予维生素D补充剂可以降低患癌症的风险。许多临床前研究表明，将癌细胞-以及源自肿瘤的血管内皮细胞-暴露于高浓度的维生素D活性代谢物会阻止细胞周期的进展，诱导细胞凋亡，并将减缓或停止体内肿瘤的生长。没有数据表明一种类型的癌症或多或少容易受到维生素D的影响。维生素D还在体内临床前模型中增强许多类型的细胞毒性抗癌剂的抗肿瘤活性。维生素D类似物通过许多重要途径启动信号传导，但维生素D抗肿瘤活性所必需的途径尚不清楚。维生素D作为抗肿瘤剂的临床研究由于缺乏合适的药物制剂而受到阻碍。所有市售制剂都是不充分的，因为必须给予大量的囊片和这些高剂量的骨化三醇（最仔细研究的类似物）的“生物利用度”差。临床前数据表明，非常高的骨化三醇暴露是必要的抗肿瘤作用。临床数据确实表明，可以安全地给予非常高剂量的钙三醇（每周静脉注射> 100微克，每周口服0.15微克/公斤）。骨化三醇的最大耐受剂量（MTD）尚不清楚。一项在去势抵抗性前列腺癌（CRPC）男性患者中进行的250例患者试验比较了多西他赛（36 mg/sqm每周一次）+/-骨化三醇0.15 mcg/kg，表明骨化三醇非常安全，可能降低了死亡率，而一项充分把握度（1000例患者）的每周一次多西他赛+骨化三醇vs每3周一次多西他赛的随机化研究结果为阴性。该试验的局限性是本研究中比较的化疗组不平等，以及未能使用最佳生物剂量或最大耐受剂量的钙三醇。鉴于大量的临床前和流行病学数据支持维生素D在癌症中的潜在作用，需要进行仔细的研究，以评估维生素D替代对癌症发生频率的影响，以及适当剂量和时间表的骨化三醇或其他活性维生素D类似物对已确定癌症治疗的影响。
Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression and therapy of cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps the most robust of these epidemiologic studies is that of Giovannucci and colleagues who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among more than 40,000 individuals in the Health professionals Study an increase in 25(OH) cholecalciferol level of 62.5ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers and acute leukemia by >50%. Unfortunately very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells – as well as vascular endothelial cells derived from tumors - to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large numbers of caplets and the poor “bioavailability” of calcitriol (the most carefully studied analogue) at these high doses. Preclinical data suggest that very high exposures to calcitriol are necessary for the antitumor effects. Clinical data do indicate that very high doses of calcitriol (>100mcg weekly, intravenously and 0.15mcg/kg weekly orally) can be given safely. The maximum tolerated dose (MTD) of calcitriol is unclear. While a 250 patient trial in men with castration resistant prostate cancer (CRPC) comparing docetaxel (36mg/sqm weekly) +/- calcitriol 0.15mcg/kg indicated that calcitriol was very safe, may have reduced to death rate, an adequately powered (1000 patients) randomized study of weekly docetaxel + calcitriol vs q3 week docetaxel was negative. The limitations of this trial were the unequal chemotherapy arms compared in this study and the failure to use an optimal biologic dose or MTD of calcitriol. In view of the substantial preclinical and epidemiologic data supporting the potential role of vitamin D in cancer, careful studies to evaluate the impact of vitamin D replacement on the frequency of cancer and the impact of an appropriate dose and schedule of calcitriol or other active vitamin D analogue on the treatment of established cancer are indicated.