WR-2721: A UNIQUE CHEMOPROTECTIVE AND HYPOCALCEMIC AGENT

WR-2721是一种有机硫代磷酸化合物，在动物模型中 选择性地保护正常组织免受 放射治疗和烷化剂化疗的因数为1.2~4.0。 基于广泛的实验室调查，第一阶段/第二阶段试验已经完成 开始确定将WR-2/21与这些抗肿瘤药物联合使用 治疗方法可能允许给药更大剂量的 化疗或放疗，导致更大比例的肿瘤细胞杀伤 具有降低寄主毒性的优点。这项研究的目标是 项目的目标是： 1)确定防护的特定剂量修正系数 WR-2721预处理的环磷酰胺的骨髓毒性 对照临床试验。目标是确定是否 超过已知耐受量的化疗剂量水平可能是 在提高治疗比率的同时给予治疗。 2)确定防护剂量修正系数 用WR-2721处理顺铂引起的肾毒性 药物是在甘露醇利尿或不利尿的情况下单次给药， 每周或每日5次给药计划。 3)启动了WR-2721的第二阶段协议， 环磷酰胺、顺铂和/或放射治疗 A组患者的客观应答率、反应持续时间、生存时间和毒性 当这些抗肿瘤药物时，单一肿瘤类型会受到显著影响 使用WR-2721。 4)在WR-2721上完成人体药代动力学数据，以确定最佳 WR-2721剂量、输液率和放射治疗与 化疗。 5)明确WR-2721产生低血钙症的机制和 WR-2721降钙剂治疗高血钙症的疗效评价 与恶毒联系在一起。 6)调查有助于提高 WR-2721和顺铂的抗肿瘤作用。以确定是否 WR-2721改变了：a)游离和蛋白质结合的顺铂药代动力学； B)顺铂排泄；c)转运至正常和恶性 纸巾。

WR-2721 is an organic thiophosphate compound which in the animal model selectively protects normal tissues against the cytotoxicity of radiotherapy and alkylating agent chemotherapy by factors of 1.2 to 4.0. Based on extensive laboratory investigation, Phase I/II trials have been initiated to determine whether combining WR-2/21 with these antineoplastic therapies may permit administration of significantly higher doses of chemotherapy or radiation, leading to greater fractional tumor cell kill with the advantage of decreased host toxicity. The goals of this research project are to: 1) Determine the specific dose modification factors for protection against bone marrow toxicity from cyclophosphamide with WR-2721 pretreatment under controlled clinical trials. The objective is to determine whether chemotherapy dose levels above those known to be tolerated can be administered with improvement of the therapeutic ratio. 2) Determine the dose modification factors for protection against cis-platinum induced nephrotoxicity with WR-2721 pretreatment when these drugs are administered in single doses with or without mannitol diuresis, and in weekly or daily x 5 dosage schedules. 3) Initiated Phase II protocols of WR-2721 with combinations of cyclophosphamide, cis-platinum and/or radiotherapy to determine whether objective response rates, response duration, survival, and toxicity in a single tumor type are significantly affected when these anti-tumor agents are administered with WR-2721. 4) Complete human pharmacokinetic data on WR-2721 to define the optimal WR-2721 dose, rate of infusion, and interval between radiotherapy and chemotherapy. 5) To define the mechanism by which WR-2721 produces hypocalcemia and evaluate the efficacy of WR-2721 as a hypocalcemic agent in hypercalcemia asssociated with malignancy. 6) To investigate possible mechanisms contributing to the enhanced antineoplastic effects of WR-2721 and cis-platinum. To determine whether WR-2721 alters: a) free and protein bound cis-platinum pharmacokinetics; b) cis-platinum excretion; and c) transport into normal and malignant tissues.