<b>Amifostine</b>  
 
Amifostine, formerly known as WR-2721, can protect cells from damage by scavenging oxygen-derived free radicals.
 
This drug arose from a United States Army nuclear warfare project was selected from more than 4,400-screened chemicals because of its superior radioprotective properties and safety profile.

Subsequently, amifostine was evaluated for its potential role in reducing the toxicity of radiation therapy as well as chemotherapeutic agents that alter the structure and function of DNA, such as alkylating agents and platinum agents. Amifostine has been evaluated as a broad-spectrum cytoprotective agent. Preclinical studies demonstrated the ability of amifostine to selectively protect almost all normal tissues except the CNS, but not cancer tissues, from the cytotoxic effects of some chemotherapeutic agents and radiation therapy.

Amifostine is a prodrug that is dephosphorylated to the active metabolite, WR-1065, by the enzyme alkaline phosphatase. WR-1065 protects cells from damage by scavenging oxygen-derived free radicals, and donating hydrogen to repair damaged target molecules. The ability of WR-1065 to be taken up in higher concentration in normal organs than in tumor tissue is how amifostine accomplishes selective protection. Essentially the uptake of WR-1065 depends upon differences in the tissue microenvironment, resulting in the slow entry of the free thiol into tumor masses.

Tumors have a relatively poor blood supply, resulting in tissue hypoxia, anaerobic metabolism, and a low [acidotic] tissue pH. The combined poor blood supply and low pH results in low rates of amifostine activation by alkaline phosphatase. Also, the distribution of alkaline phosphatase in normal and malignant tissue differs, with higher concentrations of this enzyme found in capillaries and arterioles of normal cells and lower levels of alkaline phosphatase found in tumor tissue. So selective protection is afforded normal tissues by reduced tumor metabolism of amifostine to the active protector WR-1065, and low tumor uptake of WR-1065. 
 
The result can be as much as a 100-fold greater steady concentration of the free thiol into normal organs [e.g. bone marrow, kidney, salivary glands, heart] compared with tumor tissue. Once the free thiol WR-1065 has entered a normal cell, it can bind to the active agents [e.g. alkylating agents, platinum agents, or ionizing radiation-produced-free radicals] and detoxify them. 

<b>Amifostine and Chemotherapy</b>

Amifostine should be administered IV over 15 minutes to patients in a reclining position and should be given within 30 minutes of radiation therapy or chemotherapy. <b>The plasma half-life of amifostine is approximately 1 minute in humans</b> and virtually all of the drug is cleared from the plasma within 10 minutes. <b>Because of the extremely short half-life of amifostine, protection is unlikely against drugs that have a long half-life or that require a prolonged infusion time.</b>

It is not known whether the 740 mg/m2 dose of amifostine is as effective as the 910 mg/m2 dose for protection against chemotherapy-associated toxicity. No additional benefit has been demonstrated to suggest that multiple doses of amifostine given with each chemo dose enhance amifostine effect. 
 
Amifostine may be considered for the prevention of low white cell counts in people who receive alkylating-agent chemotherapy. Alternative approaches to the administration of amifostine to protect against chemotherapy-induced neutropenia include dose reduction, particularly in the absence of a reason to maintain chemotherapy dose-intensity, or the use of hematopoietic growth factors, such as granulocyte colony-stimulating factor or GM-CSF. In addition, close monitoring, and hospitalization if necessary until satisfactory resolution of infection and neutropenia are alternative approaches to therapeutic intervention with amifostine or growth factors or dose reduction of chemotherapy.

<b>Amifostine and Radiation</b>

When given with radiation therapy, the recommended amifostine dose is 200 mg/m2/d given as a slow IV push over 3 minutes, 15 to 30 minutes before each fraction of radiation therapy. Administration of amifostine requires close patient monitoring, but side effects are fewer at this lower dose. Many patients require antiemetics. Blood pressure should be measured just before and immediately after the 3-minute amifostine infusion. The hypotension associated with amifostine at this dose is less frequent but still requires close monitoring. 

Radioprotective activity of amifostine has been seen against jejunum, colon, lung, and bone marrow in laboratory and animal studies. A series of clinical studies suggest that amifostine pretreatment is associated with reduced complications from radiation therapy in humans.

Xerostomia [very severe dry mouth] is the most common toxicity associated with radiation treatment to the head or neck. Late xerostomia reflects fibrosis of the salivary gland from radiation therapy and is usually permanent. Xerostomia results in symptoms of a dry mouth; this affects the patient's ability to eat and speak. Additionally, patients with xerostomia are at an increased risk for dental caries, oral infections, and osteonecrosis. Amifostine decreases the incidence of acute and late xerostomia in patients who undergo radiation therapy to the head or neck.

This was paraphrased from an ASCO Special Article: American Society of Clinical Oncology Clinical Practice Guidelines for the Use of Chemotherapy and Radiotherapy Protectants. http://www.asco.org./

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