Alkylating Vitamin D Derivative

描述（申请人提供）：前列腺癌是男性中最常见的癌症；也是美国男性癌症死亡的第二大原因。目前还没有批准的治疗激素难治性前列腺癌的方法。流行病学研究表明，包括前列腺癌在内的各种癌症的发病率和死亡率、日晒和维生素D的皮肤合成之间存在密切关系。维生素D的生物活性形式已被证明对癌细胞具有很强的抗增殖作用，但在治疗剂量下具有剧毒。1,25-二羟基维生素d3 -3-溴乙酸酯（1,25(OH)2D3-3-BE）是一种维生素D的类似物，通过在肿瘤细胞中烷基化维生素D受体（VDR），具有增强的抗增殖作用，同时降低全身毒性，在激素敏感和激素难耐的前列腺癌细胞中，这种化合物具有很强的生长抑制和诱导凋亡的特性。体外试验清楚地显示了它的有效性，即使与1,25-二羟基维生素D3（维生素D激素的活性形式）相比也是如此。此外，初步的体内研究表明，1,25(OH)2D3-3-BE是无毒的，并且它在小鼠异种移植模型中强烈地减少雄激素难治性肿瘤。本STTR I期申请拟进行的研究包括在纳米体中配制1,25(OH)2D3-3-BE，确定制剂中药物的生物利用度和定量，确定该化合物及其纳米体制剂在血清和肝脏匀浆中的稳定性，确定该制剂在小鼠体内的最大耐受剂量，以及评估该制剂在小鼠异种移植模型中减少前列腺肿瘤的功效。拟议研究的数据将促进这种激素敏感和激素难治性前列腺癌所有阶段的潜在治疗剂的发展。

DESCRIPTION (provided by applicant): Prostate cancer is the most prevalent cancer among men; and the second leading cause of cancer death among men in the US. There are currently no approved therapies for hormone-refractory prostate cancer. Epidemiological studies have demonstrated a strong relationship between incidence of and mortality from various cancers including prostate cancer, exposure to the sun and cutaneous synthesis of vitamin D. The biologically active form of vitamin D has been shown to have strong antiproliferative effects in cancer cells, but it is highly toxic at therapeutic doses. In vitro tests of 1,25-dihydroxyvitamin D3-3-bromoacetate (1,25(OH)2D3-3-BE), an analog of vitamin D designed to have increased antiproliferative effects while reducing systemic toxicity through alkylation of vitamin D receptor (VDR) in tumor cells, have shown that this compound has strong growth-inhibitory and apoptosis-inducing properties in hormone-sensitive and hormone- refractory prostate cancer cells. In vitro assays have clearly shown its effectiveness, even when compared to 1,25-dihydroxyvitamin D3, the active form of vitamin D hormone. Furthermore, preliminary in vivo studies showed that 1,25(OH)2D3-3-BE is non-toxic, and it strongly reduces androgen-refractory tumor in a mouse xenograft model. The proposed research in this STTR Phase I application includes formulation of 1,25(OH)2D3-3-BE in nanosomes, determination of the bioavailability and quantification of the drug in formulation, determination of the stability of this compound neat and in its nanosomal preparation in serum and liver homogenate, determination of maximum tolerated dose of the formulated drug in mice, and evaluation of the efficacy of the formulation in reducing prostate tumor in mouse xenograft models. The data generated from the proposed studies will advance the development of this potential therapeutic agent for hormone- sensitive and hormone-refractory prostate cancers at all stages.