Cytoprotective Agents Aminothiols

Organic thiols neutralize free radicals generated in tissues exposed to cytotoxic drugs. Amifostine is a phosphorylated aminothiol initially developed as a radioprotective agent at the Walter Reed Army Institute in the 1970s. Following administration, amifostine is phosphorylated by tissue alkaline phos-

phatase, an enzyme with greater activity in normal tissue than in tumor tissue. Active free thiol thus accumulates in the normal tissue, neutralizing the destructive free radicals. Thus, amifostine has been used as a radio- and cytoprotective agent for the treatment of solid tumors. In addition, amifostine protects primitive hematopoietic progenitors from chemotherapy-induced toxicity and stimulates hematopoiesis in preclinical models and in vitro studies.53

List et al. conducted a phase I/II study of 18 MDS patients with dose escalation of amifostine up to 400 mg/m2 three times a week or 740 mg/m2 weekly for 3 weeks.54 Single or multilineage responses were seen in 83% of patients receiving three times weekly doses, which were optimized at 200 mg/m2: 14 patients had a neutrophil response, 6 had improvement in thrombocy-topenia, and 5 patients had a 50% reduction in red cell transfusion requirements. Raza et al. reported the use of amifostine in combination with pentoxifylline (P), ciprofloxacin (C), and dexamethasone (D) in 35 MDS patients.55 Pentoxifylline is a xanthine derivative that interferes with the activity of proapoptotic cytokines, such as TNFa, IL-1ß, and tumor growth factor ß (TGFß). Ciprofloxacin was added as a pharmacologic inhibitor of the hepatic metabolism of pentoxifylline and dexam-ethasone to downregulate mRNA translation of TNFa. Twenty-nine patients completed at least 12 weeks of treatment; most patients had low- to intermediate-risk MDS. Pentoxifylline was given at 800 mg three times a day, ciprofloxacin 500 mg twice a day, and dexametha-sone 4 mg a day for 4 weeks was added to partial and nonresponders at 12 weeks. Amifostine was given at 200, 300, and 400 mg/m2 (i.v. or s.q.) doses three times a week along with daily PCD therapy. An improvement in cytopenias was observed in 76% of patients, and 50% of patients had a >50% decrease in transfusion requirements. However, there was no correlation seen between response rate and the dose of amifostine given.

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