Amifostine for protection from antineoplastic drug toxicity.
The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of amifostine are reviewed. Amifostine is a prodrug converted by alkaline phosphatase to the active sulfhydryl compound WR-1065. WR-1065 protects normal cells by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen, and binding to active derivatives of antineoplastic agents. The immediate conversion of amifostine to WR-1065, its small volume of distribution, and the limited amount of drug and metabolite recovered in the urine suggest that amifostine is rapidly dephosphorylated and enters cells as its active metabolite. The selectivity of amifostine for normal tissue is hypothesized to be a results of the decreased vascularity of tumors, decreased activity of alkaline phosphatase in tumor cells, and pH dependence of WR-1065 uptake. In clinical studies, amifostine decreased the frequency of cisplatin-induced nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression. Amifostine has demonstrated an ability to decrease the hematologic toxicity of cyclophosphamide, carboplatin, mitomycin, and antineoplastic drug combinations. Amifostine has FDA-approved labeling for use in reducing cumulative renal toxicity in patients receiving repeat doses of cisplatin for advanced ovarian cancer and non-small-cell lung cancer. The recommended dose in adults is 910 mg/m2 administered as a 15-minute infusion 30 minutes before the start of chemotherapy. The major adverse effects of amifostine include hypotension and emesis. The benefits of amifostine must be weighted against its potential adverse effects, and the drug's impact on the efficacy of antineoplastics should be further investigated. Amifostine has shown promise in protecting non-malignant cells from the toxic effects of antineoplastics, apparently without compromising toxicity against cancer cells.
Foster-Nora
J A
JA
University of Michigan Health System (UMHS), USA. jafoster@am.pnu.com
Siden
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R
D004999:Amifostine / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D002986:Clinical Trials as Topic; D006309:Hearing / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy / Q000556:secondary; D009369:Neoplasms / Q000188:drug therapy*; D009420:Nervous System / Q000187:drug effects; D011355:Prodrugs / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011355:Prodrugs; D011837:Radiation-Protective Agents; D004999:Amifostine