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Chemical Compound Review

AG-F-03179     2-(3- aminopropylamino)ethanethiol

Synonyms: CHEBI:72583, NSC-647527, AC1L2XJB, AC1Q7GQD, LS-65769, ...
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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


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


  1. Further evidence that the radioprotective aminothiol, WR-1065, catalytically inactivates mammalian topoisomerase II. Snyder, R.D., Grdina, D.J. Cancer Res. (2000) [Pubmed]
  2. Activation of the nuclear transcription factor kappaB (NFkappaB) and differential gene expression in U87 glioma cells after exposure to the cytoprotector amifostine. Kataoka, Y., Murley, J.S., Khodarev, N.N., Weichselbaum, R.R., Grdina, D.J. Int. J. Radiat. Oncol. Biol. Phys. (2002) [Pubmed]
  3. WR-1065, the active metabolite of amifostine (Ethyol), does not inhibit the cytotoxic effects of a broad range of standard anticancer drugs against human ovarian and breast cancer cells. Alberts, D.S., Speicher, L.A., Krutzsch, M., Wymer, J., Capizzi, R.L., Conlon, J., Barrett, A., Aickin, M. Eur. J. Cancer (1996) [Pubmed]
  4. Relationships between DNA damage and the survival of radiosensitive mutant Chinese hamster cell lines exposed to gamma-radiation: Part 2. Effect of cellular redox status. Murray, D., Prager, A., Meyn, R.E., Davison, S., Green, A.D. Int. J. Radiat. Biol. (1993) [Pubmed]
  5. Protection of human tumor cells of differing radiosensitivity by WR-1065. Murray, D., Rosenberg, E., Allalunis-Turner, M.J. Radiat. Res. (2000) [Pubmed]
  6. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. Brizel, D.M., Wasserman, T.H., Henke, M., Strnad, V., Rudat, V., Monnier, A., Eschwege, F., Zhang, J., Russell, L., Oster, W., Sauer, R. J. Clin. Oncol. (2000) [Pubmed]
  7. Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug. Calabro-Jones, P.M., Aguilera, J.A., Ward, J.F., Smoluk, G.D., Fahey, R.C. Cancer Res. (1988) [Pubmed]
  8. N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) protects thymocytes from programmed cell death. Ramakrishnan, N., Catravas, G.N. J. Immunol. (1992) [Pubmed]
  9. Delayed cytoprotection after enhancement of Sod2 (MnSOD) gene expression in SA-NH mouse sarcoma cells exposed to WR-1065, the active metabolite of amifostine. Murley, J.S., Kataoka, Y., Weydert, C.J., Oberley, L.W., Grdina, D.J. Radiat. Res. (2002) [Pubmed]
  10. Opposite effects of WR-2721 and WR-1065 on radiation-induced hypothermia: possible correlation with oxygen uptake. Kandasamy, S.B., Kumar, K.S., Hunt, W.A., Weiss, J.F. Radiat. Res. (1988) [Pubmed]
  11. Mechanisms for the oxygen radical-mediated toxicity of various thiol-containing compounds in cultured mammalian cells. Held, K.D., Biaglow, J.E. Radiat. Res. (1994) [Pubmed]
  12. Hypotensive mechanisms of amifostine. Ryan, S.V., Carrithers, S.L., Parkinson, S.J., Skurk, C., Nuss, C., Pooler, P.M., Owen, C.S., Lefer, A.M., Waldman, S.A. Journal of clinical pharmacology. (1996) [Pubmed]
  13. Radiation protection by alpha-methyl-homocysteine thiolactone in vitro. Koch, K.E., Roberts, J.C., Lubec, G. Life Sci. (1997) [Pubmed]
  14. Thiol and disulfide metabolites of the radiation protector and potential chemopreventive agent WR-2721 are linked to both its anti-cytotoxic and anti-mutagenic mechanisms of action. Grdina, D.J., Shigematsu, N., Dale, P., Newton, G.L., Aguilera, J.A., Fahey, R.C. Carcinogenesis (1995) [Pubmed]
  15. The effects of cycloheximide and WR-1065 on radiation-induced repair processes: a mechanism for chemoprevention. Murley, J.S., Grdina, D.J. Carcinogenesis (1995) [Pubmed]
  16. Hprt mutations in human T-lymphocytes reflect radioprotective effects of the aminothiol, WR-1065. Clark, L.S., Albertini, R.J., Nicklas, J.A. Carcinogenesis (1996) [Pubmed]
  17. Tissue levels of WR-1065, the active metabolite of amifostine (Ethyol), are equivalent following intravenous or subcutaneous administration in cynomolgus monkeys. Bachy, C.M., Fazenbaker, C.A., Kifle, G., McCarthy, M.P., Cassatt, D.R. Oncology (2004) [Pubmed]
  18. Effects of dose and schedule on the efficacy of ethyol: preclinical studies. Cassatt, D.R., Fazenbaker, C.A., Kifle, G., Bachy, C.M. Semin. Oncol. (2003) [Pubmed]
  19. Inhibition of spontaneous metastases formation by amifostine. Grdina, D.J., Kataoka, Y., Murley, J.S., Hunter, N., Weichselbaum, R.R., Milas, L. Int. J. Cancer (2002) [Pubmed]
  20. Interaction of amifostine and ionizing radiation on transcriptional patterns of apoptotic genes expressed in human microvascular endothelial cells (HMEC). Khodarev, N.N., Kataoka, Y., Murley, J.S., Weichselbaum, R.R., Grdina, D.J. Int. J. Radiat. Oncol. Biol. Phys. (2004) [Pubmed]
  21. WR-1065, the active form of amifostine, protects HL-60 cells but not peripheral blood mononuclear cells from radiation and etoposide-induced apoptosis. Hatoum, G.F., Nevaldine, B., Bhavsar, T., Phung, Q., Hahn, P.J. Int. J. Radiat. Oncol. Biol. Phys. (2004) [Pubmed]
  22. Differential radioprotection of cultured human diploid fibroblasts and fibrosarcoma cells by WR1065. Zhang, X., Lai, P.P., Taylor, Y.C. Int. J. Radiat. Oncol. Biol. Phys. (1992) [Pubmed]
  23. Prostaglandins protect against murine hair injury produced by ionizing radiation or doxorubicin. Malkinson, F.D., Geng, L., Hanson, W.R. J. Invest. Dermatol. (1993) [Pubmed]
  24. Protection from cellular oxidative injury and calcium intrusion by N-(2-mercaptoethyl)-1,3-propanediamine, WR 1065. Polla, B.S., Donati, Y., Kondo, M., Tochon-Danguy, H.J., Bonjour, J.P. Biochem. Pharmacol. (1990) [Pubmed]
  25. The effect of 2-[(aminopropyl)amino] ethanethiol on fission-neutron-induced DNA damage and repair. Grdina, D.J., Sigdestad, C.P., Dale, P.J., Perrin, J.M. Br. J. Cancer (1989) [Pubmed]
  26. Degradation of 2-(3-aminopropylamino)-ethanethiol (WR-1065) by Cu-dependent amine oxidases and influence on glutathione status of Chinese hamster ovary cells. Meier, T., Issels, R.D. Biochem. Pharmacol. (1995) [Pubmed]
  27. Protective effects of 2-[(aminopropyl)amino] ethanethiol against bleomycin and nitrogen mustard-induced mutagenicity in V79 cells. Nagy, B., Grdina, D.J. Int. J. Radiat. Oncol. Biol. Phys. (1986) [Pubmed]
  28. Delayed radioprotection by NFkappaB-mediated induction of Sod2 (MnSOD) in SA-NH tumor cells after exposure to clinically used thiol-containing drugs. Murley, J.S., Kataoka, Y., Cao, D., Li, J.J., Oberley, L.W., Grdina, D.J. Radiat. Res. (2004) [Pubmed]
  29. Manganese Superoxide Dismutase (SOD2)-Mediated Delayed Radioprotection Induced by the Free Thiol Form of Amifostine and Tumor Necrosis Factor alpha. Murley, J.S., Kataoka, Y., Baker, K.L., Diamond, A.M., Morgan, W.F., Grdina, D.J. Radiat. Res. (2007) [Pubmed]
  30. Effect of amifostine on the cytotoxicity of daunorubicin and daunoxome in tumor and normal cells. Angela, M., Raffaella, S., Anna, C., Mario, T., Elisabetta, C., Domenico, R., Renato, F., Daniela, D. Cancer Chemother. Pharmacol. (2006) [Pubmed]
  31. Binding of the aminothiol WR-1065 to transcription factors influences cellular response to anticancer drugs. Shen, H., Chen, Z.J., Zilfou, J.T., Hopper, E., Murphy, M., Tew, K.D. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  32. Lens epithelial cell protection by aminothiol WR-1065 and anetholedithiolethione from ionizing radiation. Belkacémi, Y., Rat, P., Piel, G., Christen, M.O., Touboul, E., Warnet, J.M. Int. J. Cancer (2001) [Pubmed]
  33. HPLC assay for 2-(3-aminopropylamino)ethanethiol (WR-1065) in plasma. McGovern, E.P., Swynnerton, N.F., Steele, P.D., Mangold, D.J. Int. J. Radiat. Oncol. Biol. Phys. (1984) [Pubmed]
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