Some pharmacologic effects of WR-2721: their role in toxicity and radioprotection.

Abstract

YUHAS, J. M., PROCTOR, J. O. AND SMITH, L. H. Some Pharmacological Effects of WR2721: Their Role in Toxicity and Radioprotection. Radiat. Res. 54, pp. 222-233 (1973). Injection of S-2-[3-aminopropylamino]ethylphosphorothioic acid (WR-2721) into BALB/c or BC3Fi mice induces a dramatic vasodilation, which is most pronounced in the spleen. This response is a component of the drug's toxic mechanism, as evidenced by the fact that splenectomy increases the tolerance of the mice to the toxic effects of the drug. Further, removal of the spleen is associated with a reduced effectiveness of the drug in terms of radioprotection, which is similar to the effects of reduced oxygen tension. Thus, at least part of the superiority of WR-2721 as a radioprotectant is due to its ability to reduce peripheral oxygen tension. Analysis of a number of phosphorothioates has demonstrated that they fall into two general categories, those that can induce the pharmacologic response and those that cannot. Each class is described by a single curve of protection versus amount of sulfur injected. The pharmacologically active drugs produce a two-component curve-an initial rapid rise followed by a less rapid increase. The second component parallels the linear curve that characterizes the entire dose range for the drugs that are not pharmacologically active. We conclude that the radioprotective effectiveness of phosphorothioates in general is determined by two factors, the amount of sulfur that can be injected and the presence or absence of the pharmacologic reaction.