WR-2721 (Ethyol®): Reduction in Toxicity of Anticancer Therapy without Loss of Efficacy

  • William McCulloch
  • Barbara Scheffler
  • Philip Schein


WR-2721 (amifostine, Ethyol) is an organic thiophosphate which selectively protects normal, but not neoplastic, tissues against the toxicity of platinum, alkylating agents and radiotherapy. This compound was originally synthesized for the Antiradiation Drug Development Program of the Walter Reed Army Institute of Research (Davidson et al., 1980), which was established to develop radioprotective agents that could be used by military personnel in the event of nuclear warfare. The rationale for its synthesis was based upon an observation made approximately 40 years ago that the sulfhydryl-amino acid, cysteine, possessed radiation protective properties (Pratt et al., 1949). It is postulated that sulfhydryl compounds, such as cysteine, protect by scavenging free radicals (Alexander et al., 1955) or, in the setting of chemotherapy, by directly binding to alkylating agents thereby preventing damage to the structure and function of critical macromolecules. Phosphorylated aminothiols, compared to simple amino acids, represented major improvements in regard to potency, tolerance and duration of action. Of the 4400 compounds tested in this program, S-2-(3-aminopropylamino)ethyl phosphorothioic acid (WR-2721) was recognized as the best radioprotective compound. WR-2721 was capable of reducing or eliminating the toxicity and lethality associated with gamma and neutron irradiation while providing an improved therapeutic index relative to earlier radioprotectors (Davidson et al., 1980). The principal shortcoming of WR-2721, which limited its use for self-administration by military populations, was the requirement that it be given intravenously. Nevertheless, the protective properties of WR-2721 for therapeutic radiation and chemotherapy, including platinum agents, were subsequently pursued.


Autologous Bone Marrow Transplantation Nitrogen Mustard Sulfhydryl Compound Simple Amino Acid Differential Protection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alexander, P., Bacq, Z.M., Cousens, S.F., Fox, M., Herve, A., Lazar, J. 1955, Mode of action of some substances which protect against the lethal effect of X-rays. Radiat. Res. 2:392–415.PubMedCrossRefGoogle Scholar
  2. Allalunis-Turner, M.J. and Siemann, D.W., 1988, Modification of cyclophosphamide-induced pulmonary toxicity in normal mice. N.C.I Monogr. 6:51–53.Google Scholar
  3. Calabro-Jones, P.M., Fahey, R.C., Smoluk, G.D., Ward, J.F., 1985, Alkaline phosphatase promotes radioprotection and accumulation of WR-1065 in V79-171 cells incubated in medium containing WR-2721, Int. J. Radt. Bio. 47:23–27.CrossRefGoogle Scholar
  4. Calabro-Jones, P.M., Aguilera, J.A., Ward, J.F., Smoluk, G.D., Fahey, R.C., 1988, Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug, Ca. Res. 48:3634–3640.Google Scholar
  5. Constine, L.S., Zagars, G., Rubin, P., Kligerman, M.M., 1986, Protection by WR-2721 of human bone marrow function following irradiation. Int. J. Radiat. Oncol. Biol. Phys., 12:1505–1508.PubMedCrossRefGoogle Scholar
  6. Davidson, D.E., Grenan, M.M., Sweeney, T.R., 1980, Biological characteristics of some improved radioprotectors in: Radiation Sensitizers: Their Use in the Clinical Management of Cancer, Masson, New York.Google Scholar
  7. Glover, D.J., Glick, J.H., Weiler, C., Hurowitz, S., Kligerman, M.M., 1986, WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled Phase II trial, J. Clin. Oncol. 4:584–588.PubMedGoogle Scholar
  8. Glover, D.J., Glick, J.H., Weiler, C., Fox, K., Guerry, D., 1987, WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma, J. Clin. Oncol. 5 (4):574–578.PubMedGoogle Scholar
  9. Grdina, D.J., Sigdestad, C.P., 1989, Radiation protectors: the unexpected benefits, Drug Metabol. Rev. 20(1):1342.CrossRefGoogle Scholar
  10. Kemp, G.M., Glover, D.J., Schein, P.S., The role of Ethiofos (WR-2721) in the reduction of combined cisplatin and cyclophosphamide toxicity, Proceedings of ASCO, Vol.9, March, 1990.Google Scholar
  11. Milas, L., Hunter, N., Stephens, C., Peters, L.J., 1984, Inhibition of radiation carcinogenesis in mice by S-2-(3-aminopropylamino)-ethyl phosphorothioic acid, Cancer Res. 44:5567–5569.PubMedGoogle Scholar
  12. Millar, J.L., McElwain, T.J., Clutterbuck, R.D., Wist, E.A, 1982, The modification of melphalan toxicity in tumor bearing mice by S-2-(3-aminopropylamino)ethyl phosphorothioic acid (WR-2721), Am. J. Clin. Oncol. (CCT) 5:321–328.CrossRefGoogle Scholar
  13. Mollman, S., Glover, D.J., Hogan, W.M., Furman, R.E., 1988, Cisplatin neuropathy. Risk factors, prognosis and protection by WR-2721. Cancer 61:2192–2195.PubMedCrossRefGoogle Scholar
  14. Nagy, B., Dale, P.J., Grdina, D.J., 1986, Protection against cis-diaminodichloroplatinum cytotoxicity and mutagenicity in V79 cells by 2-[(aminopropyl)-amino]ethanethiol. Cancer Res. 46:1132–1135.PubMedGoogle Scholar
  15. Patt, H., Ttyree, E.B., Straube, R.L., 1949, Cysteine protection against X-irradiation, Science 110:213.PubMedCrossRefGoogle Scholar
  16. Peters, G.J., van der Wilt, C.L., Gyergyay, F., van Laar, J., Pinedo, H.M., Protection by WR-2721 of the toxicity induced by the combination of cisplatin and 5-fluorouracil, Proceedings 7th International Conference on Chemical Modifiers (in press 1991).Google Scholar
  17. Pierson, M.G. and Moller, A.R., Prophylaxis of kanamycin-induced ototoxicity by a radioprotectant, Hear. Res. 4:79–87, 1981.PubMedCrossRefGoogle Scholar
  18. Shaw, L.M., Turrisi, A.T., Glover, D.J., Bonner, H.S., Norfleet, AL., Weiler, C., Kligerman, M., Human pharmacokinetics of WR-2721. Int. J. Radiat. Oncol. Biol. Phys. 12:1501–1504.Google Scholar
  19. Smoluk, G.D., Fahey, R.C., Calabro-Jones, P.M., Agquilera, J.A., Ward, J.F., 1988, Radioprotection of cells in culture by WR-2721 and derivatives: form of the drug responsible for protection, Cancer Res. 48:3641–3647.PubMedGoogle Scholar
  20. Spiritos, M, Schucter, L., Glover, D., Grabelsky, M., MacDermott, M., Weiler, C., Glick, J., A phase I trial of carboplatin and WR-2721, Proceedings of the American Society of Clinical Oncology, No. 257 (1990).Google Scholar
  21. Treskes, M., Holwerda, U., Nijtmans, Jl., Fichtinger-Schepman, A.M.J., Pinedo, H.M. and van der Vijgh, W.J.F., Modulation of cisplatin and carboplatin with WR-2721; molecular aspect, Proceedings 7th International Conference on Chemical Modifiers (in press, 1991).Google Scholar
  22. Turrisi, AT., Glover, D.J., Hurwitz, S., Glick, J., Norfleet, A.L., Weiler, G, Yuhas, J.M., Kligerman, M.M., 1986, Final report on the Phase I trial of single dose WR-2721 (S-2-(3-aminopropylamino)-ethyl phosphorothioic acid), Cancer Treatment Rpts. 70:1389–1393.Google Scholar
  23. Utley, J.F., Seaver, N., Newton, G.L., Fahey, B.C., 1984, Pharmacokinetics of WR-1065 in mouse tissue following treatment with WR-2721. Int. J. Radit. Oncol. Biol. Phys. 10:1525–1528.CrossRefGoogle Scholar
  24. Valeriote, F., Tolen, S., 1982, Protection and potentiation of nitrogen mustard cytoxicity by WR-2721. Cancer Res. 42:4330–4331.PubMedGoogle Scholar
  25. Wasserman, T.H., Phillips, T.L., Ross, G., Kane, L.J., 1981, Differential protection against cytotoxic chemotherapeutic effects on bone marrow CFU’s by WR-2721, Cancer Clin. Trials 4:3–6.PubMedGoogle Scholar
  26. Yuhas, J.M., Spellman, J.M., Culo, F., 1980, The role of WR-2721 in radiotherapy and/or chemotherapy in: Radiation Sensitizers: Their Use In the Clinical Management of Cancer, Masson, New York.Google Scholar
  27. Yuhas, J.M., 1970, Biological Factors affecting the radioprotective efficiency of S-2-(3-aminopropylamino)-ethyl phosphorothioic acid (WR-2721). LD50 doses, Radiation Res. 44:621–628.PubMedCrossRefGoogle Scholar
  28. Yuhas, J.M., 1980, Active passive absorption kinetics as the basis for selective protection of normal tissues by S-2-(3-aminopropylamino)ethylphosphorothios acid. Cancer Res. 40:1519–1524.PubMedGoogle Scholar
  29. Yuhas, J.M. and Culo, F., 1980, Selective inhibition of the nephrotoxicity of cis-dichlorodiamineplatinum (II) by WR-2721 without altering its antitumor properties. Cancer Treat. Rep. 64:57–64.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • William McCulloch
    • 1
    • 2
  • Barbara Scheffler
    • 1
    • 2
  • Philip Schein
    • 1
    • 2
  1. 1.U.S. BioscienceW. ConshohockenUSA
  2. 2.University of Pennsylvania Cancer CenterPhiladelphiaUSA

Personalised recommendations