Vitamin D and Dexamethasone in Myelodysplastic Syndromes

描述(申请人提供)：骨髓增生异常综合征(MDS) 代表了一组不同的疾病，表现为 生殖障碍。MDS造血祖细胞克隆发育异常 导致严重的细胞减少症和发展成急性骨髓性疾病的倾向 白血病。目前MDS的治疗选择有限，除骨骼外 在骨髓移植方面，没有任何一项措施比单独的支持性措施更好。 临床前研究表明，阿司匹林具有潜在的治疗作用 维生素D在MDS治疗中的应用然而，由于具有剂量限制毒性， 高钙血症，维生素D的临床试验使用了低剂量， 前景看好，但结果并不一致。我们已经开发了一种剂量方案 地塞米松和骨化三醇(维生素D的活性形式)可以增加 骨化三醇的治疗指数，并允许安全地使用5-10 骨化三醇的剂量是以前用于MDS的剂量的两倍。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。 在这个提案中，我们将测试Dex和Dex组合的假设 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MDS的II期试验。这场审判将分析 血液学反应和毒性。骨髓样本将连续进行 分析分化、细胞周期停滞和细胞凋亡。试管苗 研究将与体内反应相关。我们的希望是这些 研究将帮助我们开发一种潜在的新的、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.