WR-2721: A UNIQUE CHEMOPROTECTIVE AND HYPOCALCEMIC AGENT

WR-2721是一种有机硫磷化合物，在动物模型中

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.