Disease relevance of C07651

• These studies also suggest that WR-1065 might be expected to reduce the toxicity and clastogenicity in clinical applications of etoposide or quinolone antibiotics in dose-limiting normal tissues [1].
• METHODS AND MATERIALS: The human glioma cell line U87 was grown to confluency and then exposed to WR-1065 at a concentration of 40 microM for times ranging from 30 min to 24 h [2].
• This study tested the effect of amifostine's active metabolite, the free thiol, WR-1065, on the cytotoxicity of standard anticancer drugs against human A2780 ovarian and MCF7 breast cancer cell lines in vitro, using the well-characterised sulphorhodamine B assay [3].
• In contrast to protection by anoxia, a 30-min preirradiation treatment with WR-1065 (4 mmol dm-3) protected aerated AA8, EM9, NM2, and UV41 cells to a similar extent with respect to both cell killing and the efficiency of DNA double-strand break (dsb) induction as measured by neutral elution [4].
• In spite of their marked phenotypic differences, the two glioblastoma lines were protected equivalently ( approximately 1.8-fold) after a 30-min preirradiation treatment with 4 mM WR-1065 [5].

High impact information on C07651

• 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 [1].
• Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands [6].
• The results are consistent with uptake by nonmediated, passive diffusion of the uncharged form of WR-1065 across the plasma membrane but uptake mediated by a membrane transport system could not be rigorously excluded [7].
• N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) protects thymocytes from programmed cell death [8].
• WR-1065 protected the thymocytes from radiation-induced apoptosis when incubated with cells after irradiation but not before and/or during irradiation [8].

Chemical compound and disease context of C07651

• SA-NH mouse sarcoma cells were grown to confluence and then exposed to either 40 microM or 4 mM of WR-1065, i.e. the active thiol form of amifostine, for 30 min and then washed [9].
• The dephosphorylated metabolite of WR-2721, N-(2-mercaptoethyl)-1,3-diaminopropane (WR-1065), accentuated radiation-induced hypothermia by both routes of administration [10].
• The effect of the addition of 1 microM Cu2+ to the thiol also depends on the particular thiol: e.g., Cu2+ increases cell killing in the biphasic pattern with WR-1065; it increases the toxicity of NAC only at high thiol concentrations; and it elicits a slight toxicity in the biphasic pattern by GSH and penicillamine [11].
• Amifostine and its metabolite, WR-1065, induced dose-dependent hypotension in anesthetized rats that was not blocked by N(G)-methyl L arginine (L-NAME), an NO synthase inhibitor [12].
• This product, alpha-methyl-homocysteine thio-lactone, was tested for toxicity and radiation protective effect along with known protectors L-cysteine, cysteamine and WR 1065 in cell culture using V79-4 Chinese hamster lung cells [13].

Biological context of C07651

• Protection against mutagenesis was seen for cells incubated in medium with concentrations of added WR-1065 as low as 10 microM, where cellular levels of WRSH and WRSS became difficult to measure (< or = 5 microM) and no protection against cell killing was found [14].
• Split-dose radiation experiments, that is 8 Gy versus 4 Gy + 4 Gy separated by 3 h, were performed to evaluate and contrast the relative abilities of CHX and WR-1065, each alone or in combination, in affecting cell survival [15].
• This is the first study to demonstrate the protective effects of WR-1065 against radiation-induced mutation in a reporter gene using a human non-cycling cell [16].
• The relative plasma bioavailability of WR-1065 given subcutaneously was lower at 30 and 60 min [17].
• We have previously reported equivalence between IV and SC administration using a rat model of radioprotection and active metabolite (WR-1065) tissue pharmacokinetics [18].

Anatomical context of C07651

• Hprt mutations in human T-lymphocytes reflect radioprotective effects of the aminothiol, WR-1065 [16].
• Consistent with these affects, WR-1065 was also found to be effective in inhibiting the ability of Sa-NH cells to migrate through Matrigel membranes [19].
• Amifostine's active free thiol WR-1065 was investigated to determine its effect on radiation-induced changes in transcriptional patterns and subsequent apoptosis in human microvascular endothelial cells (HMEC) growing in vitro [20].
• WR-1065 also greatly reduced the percentage of HL-60 cells undergoing apoptosis 24 h after a 1-h exposure to 1 microM etoposide [21].
• The present studies were performed to determine whether WR1065, the dephosphorylated, free-thiol active metabolite of WR2721, could provide differential radioprotection of normal and tumor cell lines in vitro and secondly to investigate potential mechanisms for the selective nature of the radioprotection at the cellular and molecular level [22].

Associations of C07651 with other chemical compounds

• Local applications of 16-16 dm PGE2 or WR-1065 given 15 min before each radiation fraction also enhanced post-radiation hair regrowth, although systemic administration of either agent was more effective than the topical route [23].
• To test this hypothesis, we investigated the effects of WR 2721 and its dephosphorylated, active metabolite, WR 1065, in an in vitro model of oxidative injury [24].
• The effect(s) of the radioprotector 2-[(aminopropyl)amino] ethanethiol (WR 1065) on fission-neutron-induced DNA damage and repair in V79 Chinese hamster cells was determined by using a neutral filter elution procedure (pH 7.2) [25].
• Degradation of 2-(3-aminopropylamino)-ethanethiol (WR-1065) by Cu-dependent amine oxidases and influence on glutathione status of Chinese hamster ovary cells [26].
• This study examines the effects of the radioprotector 2-[(aminopropyl)amino] ethanethiol (WR-1065) on bleomycin (BLM) and nitrogen mustard- (HN2) induced cytotoxicity, DNA damage, and mutagenesis at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus in V79 Chinese hamster cells [27].

Gene context of C07651

• Effects of thiol exposure on NFKB activation in SA-NH+mIkappaBalpha1 cells were determined by a gel shift assay, and changes in Sod2 protein levels in these cells 24 h after exposure to 40 microM or 4 mM WR-1065 were measured by Western blot analysis and compared with wild-type cells exposed to the NFkappaB inhibitor BAY 11-7082 [28].
• In contrast to the robust changes observed in intracellular levels of SOD2 as a function of time after exposure of cells to WR-1065, catalase levels were elevated only 2.6-fold over background as determined by Western blot analysis, while GPX activity was unaffected by WR-1065 exposure [29].
• In conclusion these data show that the preincubation with WR-1065 does not inhibit the drug toxic effect on blast cells and on tumor cell lines, independently by their multidrug resistance phenotype, but has a cytoprotective effect on stem cells causing a drug cytotoxicity reduction of 10-20% [30].
• WR-1065, as a function of increasing dose and time, inhibited the enzymatic activities of MMP-2 and MMP-9 [19].
• However, in a transformed human tumor cell line, there was no cytoprotectivity by WR-1065, consistent with the premise that p53-dependent growth arrest is the basis for the protective effect of this compound, and that this pathway is abrogated in human tumors [31].

Analytical, diagnostic and therapeutic context of C07651

• When CHX treatment was combined with WR-1065 was abolished, that is surviving cell fraction was again reduced by approximately 60% as compared with untreated control groups [15].
• This in vitro study demonstrates that WR-1065 and ADT protects lens epithelial cells from x-ray injury; thus, ADT and amifostine are appropriate candidates for clinical trials in humans [32].
• Tissues were analyzed for free WR-1065 by reverse-phase HPLC and electrochemical detection 30 and 60 min after administration [17].
• A high pressure liquid chromatography (HPLC) plasma assay for WR-1065 is described which is both precise (coefficient of variation less than 5%) and accurate (% average deviation less than or equal to 6.1) throughout the concentration range from 1 to 500 micrograms/mL of plasma [33].
• The radioprotective drug 2-(3-aminopropylamino)ethanethiol (WR-1065) can be degraded when incubated in cell culture medium in vitro [26].

References