Vitamin D and Dexamethasone in Myelodysplastic Syndromes

描述（由申请人提供）：骨髓增生异常综合征（MDS） 代表了一组异质性疾病， 发育不良骨髓增生异常综合征造血祖细胞克隆发育异常 会导致严重的血细胞减少，并有发生急性骨髓性白血病的倾向。 白血病目前MDS的治疗选择是有限的，除了骨外， 骨髓移植，没有一个被证明上级单独的支持措施。 临床前研究表明， 维生素D治疗MDS然而，由于剂量限制性毒性， 高钙血症，维生素D的临床试验使用低剂量， 有希望但不一致的结果。我们已经制定了一个剂量方案， 地塞米松和骨化三醇（维生素D的活性形式）， 骨化三醇的治疗指数，并允许安全施用5-10 骨化三醇的剂量比以前用于MDS的剂量高一倍。我们有 还确定了地塞米松增强维生素D的活性， 鳞状细胞癌和前列腺癌的临床前模型的数量。 在本提案中，我们将检验Dex和 大剂量骨化三醇治疗MDS有效。我们在此建议 地塞米松和骨化三醇治疗骨髓增生异常综合征的II期临床试验这次审判将分析 血液学反应和毒性。骨髓样本将连续 分析分化、细胞周期停滞和凋亡。体外 研究将与体内反应相关。我们希望这些 研究将帮助我们开发出一种潜在的新颖的、口服的、毒性最小的方案， 用于治疗MDS。

DESCRIPTION (provided by applicant): The myelodysplastic syndromes (MDS) represent a heterogeneous group of diseases that manifest themselves as dyspoiesis. Abnormal clonal development of hematopoietic progenitors in MDS leads to severe cytopenias and a predisposition to develop acute myelogenous leukemia. Current therapeutic options for MDS are limited, and aside from bone marrow transplantation, none have proven superior to supportive measures alone. Preclinical investigations have indicated a potential therapeutic role for vitamin D in treatment of MDS. However, because of dose-limiting toxicity of hypercalcemia, clinical trials with vitamin D have used low doses, with promising but inconsistent results. We have developed a dosing schema of Dexamethasone and calcitriol (the active form of vitamin D) that augments the therapeutic index of calcitriol, and allows for safe administration of 5-10 times higher doses of calcitriol than has previously been used for MDS. We have also determined that Dexamethasone potentiates the activity of vitamin D in a number of preclinical models for squamous cell carcinoma and prostate cancer. In this proposal we will test the hypothesis that the combination of Dex and high-dose calcitriol will be effective for treatment of MDS. We propose herein a phase II trial of Dex and calcitriol for MDS. This trial will analyze hematologic response and toxicity. Bone marrow samples will be serially analyzed for differentiation, cell cycle arrest, and apoptosis. The in vitro studies will be correlated with in vivo response. Our hope is that these studies will help us develop a potentially novel, oral, minimally toxic regimen for treating MDS.