Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amifostine (WR-2721, Ethyol), S-2[3-aminopropylamino]-ethyl-phosphorothioic acid, was selected as a clinically usable radioprotector from more than 4,400 compounds in the 1950s. A considerable amount of preclinical work suggested that amifostine, or its activated thiol WR-1065, protected normal cells effectively against the adverse effects of irradiation and several anticancer drugs without exhibiting tumor protection. In non-randomized and randomized trials in malignant melanoma, colorectal cancer, head and neck cancer, non-small cell lung cancer, and epithelial ovarian carcinoma, amifostine significantly reduced the hematological and non-hematological toxicity of DNA-damaging agents such as alkylators, platinum compounds, or mitomycin C. In more recent studies, the drug also protected patients from side effects produced by taxanes or topoisomerase I inhibitors and is thus likely to allow higher cytostatic doses to be administered. Currently, there is no evidence that amifostine compromises the antineoplastic effect of the drugs studied. Otherwise, W/R-2721 may even improve the therapeutic efficacy of agents like cisplatin, carboplatin, or paclitaxel. Moreover, amifostine appears to produce growth-factor like properties resulting in growth-promoting effects on primitive blood progenitor cells ex vivo. Amifostine offers a rational approach to protect patients against chemotherapy-specific and often dose-limiting effects and is thus likely to improve therapeutic outcome significantly. Future studies should be focused on both new indications like childhood cancer, myelodysplastic syndromes, dose-intensified or high- dose chemotherapy, and multimodality approaches and optimization of amifostine dosage in order to reduce dose-limiting side effects. Then, the drug may play a major role in more specific and individualized oncologic strategies.
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PMID:Chemoprotection in anticancer therapy: the emerging role of amifostine (WR-2721). 970 84

Amifostine (Ethyoltrade mark, Alza Pharmaceuticals) is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[3- aminopropyl)amino]dihydrogen phosphate. It is a prodrug of free thiol (WR-1065) that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. Differences in the alkaline phosphatase concentration of normal versus tumour tissues can result in greater conversion of amifostine in normal tissues. Inside the cell, WR-1065 provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapy agents. Preclinical animal studies have demonstrated that the administration of amifostine protects against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine has been shown to protect a variety of animal species from lethal doses of radiation. Amifostine gives haematological protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin and salivary gland protection from radiotherapy. Multiple Phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine were found to be 740 - 910 mg/m(2) in single-dose regimens and 340 mg/m(2) in multiple-dose regimens. In radioprotection, doses are generally 200 - 350 mg/m(2). For all these characteristics, amifostine has been recently approved and suggested in ASCO clinical practice guidelines as a radioprotector for head and neck cancer treatment and supportive agent during cisplatin-based chemotherapy, in lymphomas and solid tumours. Moreover, its spectrum of possible applications is enlarging. As data have been provided indicating that amifostine stimulates haematopoiesis, it has been employed with intriguing results in the treatment of myelodysplastic syndromes (MDS).
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PMID:Amifostine: chemotherapeutic and radiotherapeutic protective effects. 1133