Beer Tomasz M, Myrthue Anne
Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA.
Mol Cancer Ther. 2004 Mar;3(3):373-81.
1,25-Dihydroxyvitamin D (calcitriol), the most active metabolite of vitamin D, has significant antineoplastic activity in preclinical models. Several mechanisms of activity have been proposed. These include inhibition of proliferation associated with cell cycle arrest and, in some models, differentiation, reduction in invasiveness and angiogenesis, and induction of apoptosis. Proposed mechanisms differ between tumor models and experimental conditions, and no unifying hypothesis about the mechanism of antineoplastic activity has emerged. Synergistic and/or additive effects with cytotoxic chemotherapy, radiation, and other cancer drugs have been reported. Significantly supraphysiological concentrations of calcitriol are required for antineoplastic effects. Such concentrations are not achievable in patients when calcitriol is dosed daily due to predictable hypercalcemia and hypercalcuria; however, phase I trials have demonstrated that intermittent dosing allows substantial dose escalation and has produced potentially therapeutic peak calcitriol concentrations. Recently, a phase II study reported encouraging levels of activity for the combination of high-dose calcitriol and docetaxel administered on a weekly schedule in patients with androgen-independent prostate cancer. This regimen is now under study in a placebo-controlled randomized trial in androgen-independent prostate cancer and in phase II studies in several other tumor types. Further work is needed to elucidate the molecular mechanisms of antineoplastic activity and optimal clinical applications of calcitriol in cancer.
1,25-二羟基维生素D（骨化三醇）是维生素D最具活性的代谢产物，在临床前模型中具有显著的抗肿瘤活性。已提出多种活性机制。这些机制包括抑制与细胞周期停滞相关的增殖，在某些模型中还包括诱导分化、降低侵袭性和血管生成以及诱导细胞凋亡。不同肿瘤模型和实验条件下提出的机制有所不同，尚未出现关于抗肿瘤活性机制的统一假说。有报道称骨化三醇与细胞毒性化疗、放疗及其他抗癌药物具有协同和/或相加作用。抗肿瘤作用需要显著高于生理浓度的骨化三醇。由于可预见的高钙血症和高钙尿症，当每日给予骨化三醇时，患者无法达到这样的浓度；然而，I期试验表明，间歇给药可大幅提高剂量，并产生潜在治疗浓度的骨化三醇峰值。最近，一项II期研究报告了在雄激素非依赖性前列腺癌患者中，每周给予高剂量骨化三醇和多西他赛联合治疗时令人鼓舞的活性水平。该方案目前正在雄激素非依赖性前列腺癌的安慰剂对照随机试验以及其他几种肿瘤类型的II期研究中进行研究。需要进一步开展工作以阐明骨化三醇抗肿瘤活性的分子机制及其在癌症中的最佳临床应用。
