Binding of the aminothiol WR-1065 to transcription factors influences cellular response to anticancer drugs

The aminothiol WR-1065 (the active form of amifostine) protects normal tiss ues from the toxic effects of certain cancer drugs, while leaving their ant itumor effects unchanged. The present data address the mechanism of action of this dichotomous effect. S-35-Labeled WR-1065 bound directly to the tran scription factors nuclear factor-kappaB, activator protein-1, and p53, resu lting in enhanced binding of these proteins to target regulatory DNA sequen ces and subsequent transactivation of a number of downstream genes. Since o ther small molecular thiols could mimic WR-1065, the redox potential of the sulfhydryl is an important determinant of its activity. In nontransformed cells, WR-1065 protected cells from the cytotoxic effects of paclitaxel in a p53-dependent manner. However, in a transformed human tumor cell line, th ere was no cytoprotectivity by WR-1065, consistent with the premise that p5 3-dependent growth arrest is the basis for the protective effect of this co mpound, and that this pathway is abrogated in human tumors. The combined da ta support the principle that the cellular effects of the aminothiol WR-106 5 are mediated through an impact on transcriptional regulation and are not only a consequence of radical scavenging.