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。目前还没有激素抵抗前列腺癌的已获批准的治疗方法。流行病学研究表明，前列腺癌、暴晒和皮肤合成维生素D等各种癌症的发病率和死亡率之间存在密切关系。维生素D的生物活性形式已被证明在癌细胞中具有强烈的抗增殖作用，但在治疗剂量下它具有高度毒性。1，25-二羟基维生素D3-3-溴乙酸酯(1，25(OH)2D3-3-BE)是维生素D的类似物，旨在通过肿瘤细胞中维生素D受体(VDR)的烷基化来增加抗增殖作用，同时降低全身毒性。体外试验表明，该化合物在激素敏感和激素耐药的前列腺癌细胞中具有强烈的生长抑制和诱导凋亡特性。体外试验已经清楚地表明了它的有效性，即使与维生素D激素的活性形式1，25-二羟基维生素D3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，它显著减少了小鼠异种移植模型中雄激素难治性肿瘤的发生。这一STTRI期应用的拟议研究包括：1，25(OH)2D3-3-BE纳米粒在纳米粒中的配方，制剂中药物的生物利用度和定量，该化合物及其纳米制剂在血清和肝匀浆中的稳定性，确定配方药物在小鼠体内的最大耐受量，以及评价该制剂在小鼠异种移植模型中减少前列腺癌的疗效。拟议研究产生的数据将推动这种潜在的治疗激素敏感型和激素耐药前列腺癌所有阶段的药物的发展。

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.