| Description | Amifostine, an organic thiophosphate, was introduced for the reductionof cisplatin-induced renal toxicity in patients with advanced ovarian cancer. It is also aradio-protective agent. Amifostine is a prodrug which is rapidly dephosphorylated,preferentially in non-tumor tissues to the active thiol. This agent binds tochemotherapeutic drugs and free radicals released by radiotherapy. The protectiveeffect of amifostine was observed in a wide range of normal organs including bonemarrow and gastrointestinal mucosa without interfering with the anti-tumor effect ofchemohadiotherapy, indicating an increased therapeutic index for existing cancertreatment. Amifostine is also being evaluated as a cytoprotective in other types oftumors including lung, breast, head and neck cancers. It was reported to be a potentmucolytic with potential in cystic fibrosis. |
| Chemical Properties | White Solid |
| Originator | US Bloscience (U.S.A.) |
| Uses | It is a thiophosphate derivative of cysteamine; provides normal cells with selective protection against the toxic effects of cancer chemotherapy and radiation treatment |
| Uses | neuroleptic |
| Definition | ChEBI: An organic thiophosphate that is the S-phospho derivative of 2-[(3-aminopropyl)amino]ethanethiol. A prodrug for the free thiol, WR-1065, which is used as a cytoprotectant in cancer chemotherapy and radiotherapy. |
| Manufacturing Process | A solution of 2-(3-aminopropylamino)ethanol (25.0 g, 0.212 mole) in 48 %hydrobromic acid (200 ml) was distilled until 35 ml of distillate had beencollected. The solution was refluxed and, periodically, more distillate wascollected. The total volume of distillate removed in 7 distillation periods was160 ml, or 80 % of the original volume of 48% hydrobromic acid, and thetime of continuous boiling was approximately 48 hours. The residual solutionwas then evaporated to dryness under reduced pressure with the aid ofseveral added portions of methanol. The crystalline residue was thoroughlytriturated with acetone, collected, and washed on the funnel with acetone.After the product had been pressed as dry as possible on the funnel, it wasdissolved in a slight excess of boiling methanol and the solution was filtered.Addition of acetone to the filtrate precipitated pure N-(2-bromoethyl)-1,3-propanediamine dihydrobromide as colorless crystals, which were dried invacuum over phosphorus pentoxide: yield 58.0 g (80%), melting point 205-206°C. Trisodium phosphorothioate (6.93 g, 38.5 mmoles) was graduallyadded in small portions with vigorous stirring to water (38 ml) cooledexternally by means of a water bath (15°-20°C). To the resulting suspensionwas added N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (13.3 g,38.8 mmoles). After a few minutes, complete solution occurred, and N,Ndimethylformamide(19 ml) was added with continued external cooling at 15°-20°C. After the solution had been stirred at about 20°C for 90 min, it waspoured into methanol (250 ml), and the mixture was refrigerated at 4°Covernight. The white precipitate that formed was collected and pressed as dryas possible on the funnel. The solid was dissolved in water (40 ml), and thesolution was filtered. Addition of methanol (250 ml) reprecipitated theproduct. After the mixture had been refrigerated about 1 hour, the productwas collected and washed on the funnel, first with methanol and finally withether. The white solid was dried in vacuo at room temperature, then exposedto ambient conditions of the laboratory for 5 hours, and bottled undernitrogen and stored in a freezer. The yield of S-2-(3-aminopropylamino)ethyldihydrogen phosphorothioate monohydrate, melting point (from methanol)160-161°C, dec., was 8.15 g (91%). |
| Brand name | Ethyol (MedImmune) [USAN previously used: Ethiofos.]. |
| Therapeutic Function | Radioprotective, Chemoprotectant, Mucolytic |
| Safety Profile | Poison by intravenous,intramuscular, and intraperitoneal routes. Moderately toxicby ingestion. An experimental teratogen. Otherexperimental reproductive effects. Mutation data reported. When heated todecomposition it emits very toxic fumes of SOx, PO |
| storage | Store at +4°C |
| References | [1] Chemoprotective and radioprotective effects of amifostine: an update of clinical trials
[2] MAURO PROVINCIALI . In vivo amifostine (WR-2721) prevents chemotherapy-induced apoptosis of peripheral blood lymphocytes from cancer patients[J]. Life sciences, 1999, 64 17: Pages 1525-1532. DOI:10.1016/s0024-3205(99)00096-x
[3] MICHAEL I KOUKOURAKIS. Amifostine before chemotherapy: improved tolerance profile of the subcutaneous over the intravenous route.[J]. Clinical Cancer Research, 2003, 9 9: 3288-3293.
[4] DANIELA MAURICI. Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay[J]. Oncogene, 2001, 20 27: 3533-3540. DOI:10.1038/sj.onc.1204428 |
