CALCIDIOL THERAPY FOR PROSTATE CANCER

申请人的描述（Applicant's Description） 雄激素非依赖性前列腺癌的有效治疗是迫切需要的。 needed. 首席研究员率先提出了一个假设， 维生素D的激素形式，1，25-二羟基维生素D（1，25（OH）2-D），调节 前列腺细胞的生长和正常分化。 这一证据 包括普遍存在的1，25（OH）2D（VDR）受体， 1，25（OH）_2D对前列腺增生和分化的抑制作用 细胞在体外和体内。 这些研究结果强烈支持使用 1，25（OH）2D在前列腺癌治疗中的应用 然而，在男性中使用1，25（OH）2D 高钙血症的风险限制了前列腺癌的治疗。 首席研究员最近证明前列腺癌细胞 从其前体25-羟基维生素D（25-OH-D）合成1，25（OH）2.D，还 称为骨化二醇）。 此外，我们发现，在体外， 通过显著抑制增殖来响应25-OH-D。 这些 研究结果对前列腺癌治疗具有重要意义，因为25- OH-D比1，25（OH）2D具有更低的高钙血症风险。 我们 假设25-OH-D将抑制人 将前列腺癌细胞异种移植到裸鼠体内。此外，我们假设 25-OH-D不会引起血清1，25（OH）2D和血钙升高。 本研究的具体目标是： 1. 比较治疗的小鼠中异种移植的人前列腺肿瘤的生长 25-OH-D与安慰剂对照。 2.通过测定血清1，25（OH）2D确定25-OH-D可能的毒性， 钙和体重。 3. 将25-OH-D治疗与异种移植物中的肿瘤标志物以及 正常小鼠前列腺的组织学分化。

DESCRIPTION (Applicant's Description) Effective therapies for androgen-independent prostate cancer are urgently needed. The principal investigator has pioneered the hypothesis that the hormonal form of vitamin D, 1,25-Dihydroxyvitamin D (1,25(OH)2-D), modulates the growth and normal differentiation of prostatic cells. This evidence includes the ubiquitous presence of receptors for 1,25(OH)2D (VDRs), and the antiproliferative and prodifferentiating effects of 1,25(OH)2D in prostatic cells in vitro and in vivo. These findings strongly support the use of 1,25(OH)2D in prostate cancer therapy. However, the use of 1,25(OH)2D in men with prostate cancer is limited by the risk of hypercalcemia. The principal investigator recently demonstrated that prostate cancer cells synthesize 1,25(OH)2.D from its precursor, 25-Hydroxyvitamin D (25-OH-D, also known as calcidiol). Moreover, we showed that in vitro, prostate cells respond to 25-OH-D by a significant inhibition of proliferation. These findings have important implications for prostate cancer therapy because 25- OH-D carries a much lower risk of hypercalcemia than 1,25(OH)2D. We hypothesize that 25-OH-D will inhibit the in vivo proliferation of human prostate cancer cells xenografted into nude mice. Furthermore, we hypothesize that 25-OH-D will not cause elevations in serum 1,25(OH)2D and serum calcium. The Specific Aims of this research are to: 1. Compare the growth of xenografted human prostatic tumors in mice treated with 25-OH-D vs. placebo control. 2. Determine the possible toxicity of 25-OH-D by measuring serum 1,25(OH)2D, calcium, and body weight. 3. Correlate 25-OH-D treatment with tumor markers in the xenografts and with histological differentiation of the normal mouse prostates.