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Chemical Compound Review

Ethiofos     2-(3-aminopropylamino) ethylsulfanylphospho...

Synonyms: Gammaphos, Apaetp, Ethyol, amifostine, WR-2721, ...
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Disease relevance of Gammaphos

  • We investigated the causes of the hypocalcemia associated with WR-2721, an investigational drug that protects normal tissues against the toxic effects of radiation and chemotherapy [1].
  • WR-2721 could therefore be an effective drug to treat human hypercalcemia of malignancy, particularly in those tumors wherein a markedly enhanced renal Ca reabsorption contributes to the elevation of the plasma Ca level [2].
  • Bone resorption by primary culture of chick osteoclasts was inhibited by WR 2721 at concentrations as low as 10(-4) M in the absence of hormonal stimulation [3].
  • Intracolonic WR 2721 protection of the rat colon from acute radiation injury [4].
  • These data demonstrate that WR 2721 exerts its radioprotective effect without the coincident development of secondary tissue hypoxia and provide rationale for a clinical trial in humans [4].

Psychiatry related information on Gammaphos


High impact information on Gammaphos

  • We conclude that WR-2721 inhibits the secretion of parathyroid hormone and enhances calciuria, thereby leading to hypocalcemia [1].
  • These results suggest that in this HHM model, WR-2721 can normalize calcemia through its PTH-independent inhibitory effect on TRCa [2].
  • (b) In intact rats a maximal hypocalcemic dose of WR-2721 reduced urinary cyclic AMP excretion from 70.5 +/- 6.3 to 38.2 +/- 3.1 pmol/ml glomerular filtration rate (GFR), a level comparable to that observed (35.9 +/- 5.2 pmol/ml GFR) in thyroparathyroidectomized (TPTX) rats [8].
  • After several days of saline diuresis the patient received WR-2721, 740 mg/m2 over 15 minutes, resulting in a fall in serum calcium from 11.76 to 9.06 mg/dL within 24 hours [9].
  • It is concluded that if WR-2721 is capable of selectively protecting nontumor tissue from the toxicities of platinum-based chemotherapy, it is doing so by some mechanism other than its selective uptake into normal tissue and subsequent nonspecific inactivation of any reactive cytosolic platinum species formed [10].

Chemical compound and disease context of Gammaphos


Biological context of Gammaphos


Anatomical context of Gammaphos


Associations of Gammaphos with other chemical compounds

  • In order to convert WR-2721 to the free thiol compound (WR-1065) in vitro, the medium also contained 20 U/ml alkaline phosphatase (AP) [21].
  • In vitro metabolism of the phosphorothioate radioprotectors WR-2721 and WR-3689 [23].
  • Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response [24].
  • Three weeks after systemic administration of 16-16 dm PGE2 (Upjohn Company) or WR-2721, given 1 h before each dose of 2-4.5 Gy per fraction for 10-15 fractions, regrowing hair counts increased up to 100% compared to irradiated-only skin sites [25].
  • Cisplatin "rescue" was demonstrated by DDTC, WR-2721 and 5-TG, and enhanced effects on the inhibition of tumor growth resulted when 20 mg/kg cisplatin and 730 mg/kg DDTC were combined with radiotherapy [26].
  • The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from the plasma data were 107 L/h/m(2), 5.53 L/m(2), and 30.6 L/h/m(2) [27].

Gene context of Gammaphos

  • In contrast, the abundance of IAP expression in normal tissues, stromal and vascular, ensures an intense hydrolysis of WR-2721 and rapid intracellular accumulation of WR-1065 [28].
  • In incubations with fetal rat long bone labeled in utero with 45Ca, 10(-3) M WR 2721 inhibited PTH-stimulated, but not base-line release of 45Ca [3].
  • Several approaches to decrease the myelotoxicity of chemo- and/or radiotherapy were discussed: MDR gene therapy, use of chemical compounds (AS101, WR 2721), cytokines such as TNF alpha and IL-1 and small peptides, pEEDCK and AcSKDP [29].
  • Plasma concentrations of three other hormones, i.e. renin, insulin, and prolactin, were not affected by the administration of WR-2721 [30].
  • PURPOSE: This study tests the hypothesis that p53 status, i.e. wild type versus mutant form, is a determinant in radiation protection of human glioma cells by WR-1065, the active thiol form of amifostine (WR-2721) [31].

Analytical, diagnostic and therapeutic context of Gammaphos

  • Intravenous injection of 30 mg/kg WR 2721 in rats and 15 mg/kg in dogs lowers serum calcium by 19 and 25%, respectively [3].
  • The reverse-phase HPLC peak, which behaved chromatographically as a Pt(dach)(WR-1065) standard, was less prominent after the i.v. administration of WR-2721 than it was after i.p. administration under any of the paradigms tested [10].
  • The results suggest that ethiofos sensitized SCLC cells to LAMP; thus ethiofos-enhanced LAMP may be an effective method for removing metastatic SCLC cells from bone marrow used for autologous marrow transplantation after high dose chemotherapy [13].
  • We sought to determine if WR-2721 would decrease bone loss in an animal model of disuse osteoporosis produced by unilateral knee tenotomy in the rat [32].
  • The ability of WR-2721 to prevent radiation-induced immunosuppression, metastatic spread, and carcinogenesis are additional benefits in the therapeutic use of this agent [33].


  1. Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent). Glover, D., Riley, L., Carmichael, K., Spar, B., Glick, J., Kligerman, M.M., Agus, Z.S., Slatopolsky, E., Attie, M., Goldfarb, S. N. Engl. J. Med. (1983) [Pubmed]
  2. Normalization of hypercalcemia associated with a decrease in renal calcium reabsorption in Leydig cell tumor-bearing rats treated with WR-2721. Hirschel-Scholz, S., Caverzasio, J., Rizzoli, R., Bonjour, J.P. J. Clin. Invest. (1986) [Pubmed]
  3. Bone and parathyroid inhibitory effects of S-2(3-aminopropylamino)ethylphosphorothioic acid. Studies in experimental animals and cultured bone cells. Attie, M.F., Fallon, M.D., Spar, B., Wolf, J.S., Slatopolsky, E., Goldfarb, S. J. Clin. Invest. (1985) [Pubmed]
  4. Intracolonic WR 2721 protection of the rat colon from acute radiation injury. France, H.G., Jirtle, R.L., Mansbach, C.M. Gastroenterology (1986) [Pubmed]
  5. Toxicity and biodistribution of the radioprotectors, WR2721, WR77913, and WR3689, in the CNS following intraventricular or intracisternal administration. Spence, A.M., Edmondson, S.W., Krohn, K.A., Grunbaum, Z., Rasey, J.S., Steele, J.E. Int. J. Radiat. Oncol. Biol. Phys. (1986) [Pubmed]
  6. Behavioral toxicity and efficacy of WR-2721 as a radioprotectant. Bogo, V., Jacobs, A.J., Weiss, J.F. Radiat. Res. (1985) [Pubmed]
  7. Dose and time relationships of the radioprotector WR-2721 on locomotor activity in mice. Landauer, M.R., Davis, H.D., Dominitz, J.A., Weiss, J.F. Pharmacol. Biochem. Behav. (1987) [Pubmed]
  8. Inhibition of parathyroid hormone secretion and parathyroid hormone-independent diminution of tubular calcium reabsorption by WR-2721, a unique hypocalcemic agent. Hirschel-Scholz, S., Caverzasio, J., Bonjour, J.P. J. Clin. Invest. (1985) [Pubmed]
  9. Treatment of hypercalcemia in parathyroid cancer with WR-2721, S-2-(3-aminopropylamino)ethyl-phosphorothioic acid. Glover, D.J., Shaw, L., Glick, J.H., Slatopolsky, E., Weiler, C., Attie, M., Goldfarb, S. Ann. Intern. Med. (1985) [Pubmed]
  10. Effect of the chemoprotective agent WR-2721 on disposition and biotransformations of ormaplatin in the Fischer 344 rat bearing a fibrosarcoma. Thompson, D.C., Wyrick, S.D., Holbrook, D.J., Chaney, S.G. Cancer Res. (1995) [Pubmed]
  11. WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma. Glover, D., Glick, J.H., Weiler, C., Fox, K., Guerry, D. J. Clin. Oncol. (1987) [Pubmed]
  12. Clinical trial of the effect of S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR-2721) (NSC 296961) on the toxicity of cyclophosphamide. Woolley, P.V., Ayoob, M.J., Smith, F.P., Dritschilo, A. J. Clin. Oncol. (1983) [Pubmed]
  13. Purging of small cell lung cancer cells from human bone marrow using ethiofos (WR-2721) and light-activated merocyanine 540 phototreatment. Meagher, R.C., Rothman, S.A., Paul, P., Koberna, P., Willmer, C., Baucco, P.A. Cancer Res. (1989) [Pubmed]
  14. Pharmacokinetics of WR-2721. Shaw, L.M., Glover, D., Turrisi, A., Brown, D.Q., Bonner, H.S., Norfleet, A.L., Weiler, C., Glick, J.H., Kligerman, M.M. Pharmacol. Ther. (1988) [Pubmed]
  15. Protection from progressive renal failure and hyperparathyroid bone remodeling by WR-2721. Hirschel-Scholz, S., Charhon, S., Rizzoli, R., Caverzasio, J., Paunier, L., Bonjour, J.P. Kidney Int. (1988) [Pubmed]
  16. Protection of acute and late radiation damage of the gastrointestinal tract by WR-2721. Ito, H., Meistrich, M.L., Barkley, H.T., Thames, H.D., Milas, L. Int. J. Radiat. Oncol. Biol. Phys. (1986) [Pubmed]
  17. 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]
  18. Radioimmunotherapy of human colorectal carcinoma xenografts using 90Y-labeled monoclonal antibody CO17-1A prepared by two bifunctional chelate techniques. Lee, Y.C., Washburn, L.C., Sun, T.T., Byrd, B.L., Crook, J.E., Holloway, E.C., Steplewski, Z. Cancer Res. (1990) [Pubmed]
  19. WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial. Glover, D., Glick, J.H., Weiler, C., Hurowitz, S., Kligerman, M.M. J. Clin. Oncol. (1986) [Pubmed]
  20. Protective effects of S-2-(3-aminopropylamino)ethylphosphorothioic acid against radiation damage of normal tissues and a fibrosarcoma in mice. Milas, L., Hunter, N., Reid, B.O., Thames, H.D. Cancer Res. (1982) [Pubmed]
  21. Promotion of cystine uptake, increase of glutathione biosynthesis, and modulation of glutathione status by S-2-(3-aminopropylamino)ethyl phosphorothioic acid (WR-2721) in Chinese hamster cells. Issels, R.D., Nagele, A. Cancer Res. (1989) [Pubmed]
  22. Protection by S-2-(3-aminopropylamino)ethylphosphorothioic acid against radiation- and cyclophosphamide-induced attenuation in antitumor resistance. Milas, L., McBride, W.H., Hunter, N., Ito, H. Cancer Res. (1984) [Pubmed]
  23. In vitro metabolism of the phosphorothioate radioprotectors WR-2721 and WR-3689. Livesey, J.C., Rasey, J.S., Vertrees, S., Freeman, L.M., Magee, S., Nelson, N.J., Chin, L., Grunbaum, Z., Krohn, K.A. Pharmacol. Ther. (1988) [Pubmed]
  24. Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome. Culy, C.R., Spencer, C.M. Drugs (2001) [Pubmed]
  25. 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]
  26. Enhancement of the potentiation of radiotherapy by platinum drugs in a mouse tumor. Douple, E.B., Richmond, R.C. Int. J. Radiat. Oncol. Biol. Phys. (1982) [Pubmed]
  27. Clinical pharmacokinetics of amifostine and WR1065 in pediatric patients with medulloblastoma. McKibbin, T., Panetta, J.C., Fouladi, M., Gajjar, A., Bai, F., Okcu, M.F., Stewart, C.F. Clin. Cancer Res. (2010) [Pubmed]
  28. Down-regulation of intestinal-type alkaline phosphatase in the tumor vasculature and stroma provides a strong basis for explaining amifostine selectivity. Giatromanolaki, A., Sivridis, E., Maltezos, E., Koukourakis, M.I. Semin. Oncol. (2002) [Pubmed]
  29. Bone marrow protection. Guigon, M., Lemoine, F., Najman, A. Bone Marrow Transplant. (1994) [Pubmed]
  30. Hypocalcaemic effect of WR-2721, S-2 (3-aminopropylamino) ethyl-phosphorothioic acid in an anuric haemodialysis patient. Zingraff, J., Bourdeau, A., Clair, F., Kindermans, C., Buisson, C., Manganella, G., Sachs, C., Drüeke, T. Nephrol. Dial. Transplant. (1987) [Pubmed]
  31. Cytoprotection by WR-1065, the active form of amifostine, is independent of p53 status in human malignant glioma cell lines. Kataoka, Y., Murley, J.S., Patel, R., Grdina, D.J. Int. J. Radiat. Biol. (2000) [Pubmed]
  32. WR-2721 reduces bone loss after hindlimb tenotomy in rats. Shaker, J.L., Fallon, M.D., Goldfarb, S., Farber, J., Attie, M.F. J. Bone Miner. Res. (1989) [Pubmed]
  33. Radioprotectors in tumor radiotherapy: factors and settings determining therapeutic ratio. Milas, L., Murray, D., Brock, W.A., Meyn, R.E. Pharmacol. Ther. (1988) [Pubmed]
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