When V79-171 cells are incubated in medium to which WR-1065 has been added the cells accumulate WR-1065 and disulfides of WR-1065 (WRSS) in a ratio of about 10:1. Analysis of the culture medium showed that it contained primarily WR-1065 but that significant levels of the symmetrical disulfide WR-33278 and of the mixed disulfide of WR-1065 with cysteine were also present. Since incubation of cel...

Aminothiols, such as WR-2721 and its active free thiol, WR-1065, reduce mutations from ionizing radiation in exponentially growing cells. In this study, human noncycling G0 T lymphocytes were exposed in vitro to gamma-irradiation in the presence or absence of WR-1065. The five treatment groups were: (a) control; (b) treatment with 4 mM WR-1065; (c) treatment with 3 Gy of gamma-radiation, from a...

Aminothiols such as WR-2721 and its active free thiol WR-1065 have previously been shown to reduce mutations resulting from ionizing radiation in exponentially growing cells. In this study, non-dividing human G0 T-lymphocytes were exposed to the aminothiol radioprotective agent, WR-1065, 30 min before or 3 h after external beam gamma-irradiation and subsequently assessed for survival and mutati...

PURPOSE Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. It was hypothesized that amifostine may be a good candidate for regional drug delivery to the liver because of its large hepatic extraction and ...

Studies of V79-171 cells were undertaken to determine what extracel lular or intracellular derivative of the drug WR-2721 is associated with radioprotection. The effect of preincubation at 23 ±1°Cwith WR-2721, and with derivatives of WR-2721 produced in medium containing alkaline phosphatase, upon survival of cells following subsequent -y-irradiation was examined. It was established that WR-2...

The aminothiol WR-1065 (the active form of amifostine) protects normal tissues from the toxic effects of certain cancer drugs, while leaving their antitumor effects unchanged. The present data address the mechanism of action of this dichotomous effect. (35)S-Labeled WR-1065 bound directly to the transcription factors nuclear factor-kappaB, activator protein-1, and p53, resulting in enhanced bin...

A liquid chromatographic method using electrochemical detection is presented for measuring the thiol WR-1065 12-(3-aminopropylamino) ethanethiol] and its symmetrical disulfide WR-33278 [NH2(CH2)3NHCH2CH2S]2. WR- 1065 is the active, radioprotective drug derived from the phosphorothioate pro-drug WR-2721 (amifostine). External standard curves for both compounds were linear over the range of 40-20...

It has recently been proposed that the thiol form of the cytoprotective drug amifostine that is designated WR-1065 [2-((aminopropyl)amino)ethanethiol] exerts its cytoprotective effects in part via a catalytic inhibition of DNA topoisomerase II (topo II)alpha. This in turn leads to the subsequent accumulation of cells in G2 phase and a prolongation of the cell cycle. We have used a Chinese hamst...

Gamma-irradiation, glucocorticoid hormones, and calcium ionophores stimulate a suicide process in thymocytes, known as apoptosis or programmed cell death, that involves internucleosomal DNA fragmentation by a Ca(2+)- and Mg(2+)-dependent nuclear endonuclease. In this study we report that N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) blocked DNA fragmentation and cell death in thymocytes expo...

In order to evaluate the anti-mutagenic effects of the potential chemoprotective compounds selenium and (S)-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-1065), CHO AA8 cells were exposed to both compounds either individually or in combination prior to irradiation. Mutation frequency following exposure to 8 Gy was evaluated by quantitation of the mutations detected at the hprt locus of th...