Commentary: The Pharmacological Antioxidant Amifostine—Implications of Recent Research for Integrative Cancer Care

Abstract

Amifostine is a pharmacological antioxidant used as a cytoprotectant in cancer chemotherapy and radiotherapy. It is thought to protect normal tissues relative to tumor tissue against oxidative damage inflicted by cancer therapies by becoming concentrated at higher levels in normal tissues. The degree to which amifostine nevertheless accumulates in tumors and protects them against cancer therapies has been debated. Guidelines have been published that direct its use in chemotherapy and radiation, taking into consideration the concerns of tumor protection. In this article, clinical studies of amifostine appearing since the publication of the most recent set of guidelines are reviewed. Randomized and nonrandomized trials of regimens involving chemo-therapeutic agents (chemotherapy, chemoradiation, conditioning regimens for bone marrow transplant) are discussed. Nineteen studies showed positive effects for amifostine reducing the level of side effects of these regimens, while 9 showed no effect and 1 had a questionable result. Clinically relevant levels of amifostine toxicity were observed in several studies, but subcutaneous administration may reduce such toxicity. Amifostine showed protection against mucositis, esophagitis, neuropathy, and other side effects, although protection against cisplatin-induced ototoxicity was not observed. No evidence of tumor protection was observed. Amifostine may enable populations unable to tolerate conventional cancer therapy to receive treatment of their cancers, even if some degree of tumor protection is eventually discovered. The authors discuss the implications of this research for patient populations seen in integrative cancer care centers and for research on phytochemical antioxidants such as vitamins and carotenoids.

Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update

“…An in vitro study demonstrated that amifostine inhibits DNA platination and is also able to reverse part of the cisplatin-DNA adducts formed, but different from the other thiols tested (DDTC and STS), and amifostine does not interfere in the antitumor efficacy of cisplatin. Additionally, clinical studies with amifostine have not provide the evidence of impairment of antitumor activity (Block and Gyllenhaal 2005). The relative success of amifostine has been attributed to the selective formation, uptake, and accumulation of the active metabolite WR1065 in normal tissues (Treskes et al 1992;Block and Gyllenhaal 2005).…”

“…Additionally, clinical studies with amifostine have not provide the evidence of impairment of antitumor activity (Block and Gyllenhaal 2005). The relative success of amifostine has been attributed to the selective formation, uptake, and accumulation of the active metabolite WR1065 in normal tissues (Treskes et al 1992;Block and Gyllenhaal 2005).…”

“…Severe nephrotoxicity, among other toxicities, has been reported in some patients treated with cisplatin despite the use of the drug (Sastry and Kellie 2005;Katzenstein et al 2009). The side effects of amifostine might be serious and include severe hypotension, ototoxicity, nausea, dizziness, vomiting, transient decrease in serum calcium levels, infusion-related flushing, and skin reactions (Gandara et al 1990;Kemp et al 1996;Block and Gyllenhaal 2005;Hausheer et al 2011b). Subcutaneous administration seems to reduce its toxicity (Block and Gyllenhaal 2005).…”

“…However, the conventional measures of hydration and osmotic diuresis are not enough to prevent a significant decrease in glomerular filtration rate after a single cycle of cisplatin-containing chemotherapy (Benoehr et al 2005). The cytoprotectant amifostine is also used to reduce nephrotoxicity when high doses of cisplatin are used, in general when doses of cisplatin are above 100 mg/m 2 or cumulative doses are above 300 mg/m 2 (Block and Gyllenhaal 2005).…”

Ameliorative effect of ginsenoside RT-5 on CDDP-induced nephrotoxicity

“…It was well documented that CDDP could be selectively accumulated in the kidney to a higher level, in which the abundant and abnormal production of ROS directly involves in the oxidative damage of cellular macromolecules, and then induces the proximal tubule necrosis and/or apoptosis [1,3] . Indeed, several antioxidant agents have been reported to ameliorate the nephrotoxicity of CDDP, such as cilastatin [7] , sildenafil [8] and amifostine (WR 2721), which was approved by FDA to reduce the cumulative nephrotoxicity induced by CDDP via scavenging the free radicals [9] . Novel antioxidants, therefore, might be potential chemoprotectants for preventing the kidney injury induced by CDDP [9,10] .…”