CALCITRIOL IN RECURRENT PROSTATE CANCER

局部前列腺癌的初始治疗以手术或放射治疗为目标。 明确治疗后，血清前列腺特异性抗原（PSA）可用于监测复发。 一旦发生转移，没有有效的治疗方法。 激素剥夺是晚期前列腺癌伴疼痛性骨转移的男性的标准治疗。 然而，早期应用雄激素剥夺并没有显示出延长PSA升高患者的生存期，PSA升高是复发的唯一证据。 需要新的药物来延缓该患者人群中前列腺癌的进展。骨化三醇是膳食维生素D的活性代谢物。 包括前列腺癌在内的许多人类肿瘤都含有骨化三醇的细胞内核受体维生素D受体（VDR）。 骨化三醇是一种在各种组织培养和癌症动物模型（包括前列腺癌）中的活性抗癌剂。 以前尝试使用骨化三醇作为人体内的抗钙药物，但当按照标准的每日时间表使用该药物时，高钙血症的发生使其失败。 临床前数据表明，间歇性暴露于高水平的骨化三醇可能足以达到抗癌效果。我们已经完成了一项在晚期恶性肿瘤患者中每周口服高剂量骨化三醇（Rocaltrol）的I期试验。虽然这种药物可以逐步增加到每周至少2.0 mg/kg，持续4周，毒性最小，但骨化三醇的吸收是非线性的，II期试验推荐0.5 ug/kg的剂量。 在该剂量下，达到了高于正常值约30的潜在治疗峰值钙三醇水平和高于正常值6-8倍的48小时AUC。 我们建议测试脉冲骨化三醇在前列腺癌确定性治疗后PSA升高的男性中的疗效。 主要终点将是PSA下降和PSA斜率。 次要终点将包括疾病进展时间和生活质量。 该研究还将密切监测长期冲击骨化三醇治疗的可能不良反应。 如果脉冲骨化三醇证明对早期转移性前列腺癌有效，未来的研究将检查其在晚期转移性前列腺癌和其他恶性肿瘤中的有用性，并检查脉冲骨化三醇与其他具有抗前列腺癌活性的药物的有希望的组合。

Initial treatment of localized prostate cancer with surgery or radiation has cure as its goal. After definitive treatment, serum prostate specific antigen (PSA) can be used to monitor for recurrence. No effective cure is available once metastases occur. Hormonal deprivation is standard treatment for men with advanced prostate cancer with painful bone metastases. However, the early application of androgen deprivation has not been shown to prolong survival in patients with rising PSA as the only evidence of recurrence. Novel agents are needed to delay the progression of prostate cancer in this patient population. Calcitriol is the active metabolite of dietary Vitamin D. Many human tumors, including prostate carci-omas, contain the intracellular nuclear receptor for calcitriol, Vitamin D receptor (VDR). Calcitriol is an active antineoplastic agent in a variety of tissue culture and animal models of cancer including adenocarcinoma of the prostate. Previous attempts to use calcitriol as an antineoplastic drug in humans have been foiled by the development of hypercalcemia when the drug is used on its standard daily schedule. Preclinical data suggest that intermittent exposure to high levels of calcitriol may be sufficient to achieve an anti-cancer effect. We have completed a Phase I trial of high-dose weekly oral calcitriol (Rocaltrol) in patients with advanced malignancies. Although this drug can be escalated to at least 2.0 mg/kg weekly for four weeks with minimal toxicity, calcitriol absorption is non-linear and a dose of 0.5 ug/kg is recommended for a Phase II trial. At this dose, potentially therapeutic peak calcitriol levels of approximately 30 above normal and forty-eight hour AUC of 6-8 fold above normal are achieved. We propose to test the efficacy of pulse calcitriol in men with rising PSA after definitive treatment for prostate cancer. The primary end point will be PSA decline and PSA slope. Secondary end points will include time to progression and quality of life. The study will also closely monitor for possibly adverse effects of prolonged pulse calcitriol therapy. If pulse calcitriol proves efficacious with early metastatic prostate cancer, future studies will examine its usefulness in advanced metastatic prostate cancer and in other malignancies as well as examine promising combinations of pulse calcitriol with other agents with activity against prostate cancer.