Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amifostine (WR-2721, S-2 [3-aminopropylamino]-ethylphosphorothioic acid; Ethyol, US Bioscience, Inc. West Conshohocken, PA), developed as a radiation protector, has exhibited activity as a chemoprotector. The compound requires activation by dephosphorylation to produce the free thiol, WR-1065. This process is catalyzed by capillary alkaline phosphatase that is close to the desired site of protection. Additionally, the neutral pH of normal tissues, compared with the slightly acidic pH of tumors, favors selective activation. The protective mechanism against radiation damage is produced, and is, most probably, different from that of chemotherapy. The most likely mechanism for radioprotection involves free radical scavenging and hydrogen donation to repair damaged DNA. The hydrogen ion donation by the thiol group is required for both chemoprotection and radioprotection. Chemoprotection is presumed to be mediated by inactivation of the charged carbonium ions of activated alkylating agents through a nucleophilic attack, thereby protecting the nucleic acids from alkylation. Amifostine is able to reduce DNA platination when preincubated or coincubated with cisplatin, but this effect is much weaker when given postincubation. Observations show that maximum protection can only be obtained if amifostine is given before the administration of cytotoxic therapy. Amifostine side effects, as seen in mice, are dose dependent. A dose of 200 mg/kg has been found to be relatively nontoxic, although some hypothermia was observed.
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PMID:Protection of normal tissues from the cytotoxic effects of chemotherapy and radiation by amifostine (Ethyol): preclinical aspects. 797 74

Amifostine (Ethyol, ALZA Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) is a phosphorylated cysteamine derivative that was originally developed by the US Army Walter Reed Institute (Washington, DC) as a radioprotectant. Amifostine, a prodrug, is metabolized by the enzyme alkaline phosphatase to an active sulfhydryl compound (WR-1065) capable of scavenging radiation-generated free radicals and preventing cell damage. The disulfides of WR-1065 are structurally analogous to endogenous polyamines, which can bind to DNA molecules and stabilize them in a compact form less vulnerable to damage by cytotoxic agents. Preclinical and clinical studies show that amifostine is a selective radioprotectant that reduces both early and late radiation-induced toxicities to normal tissues while leaving tumor cells exposed to the cytotoxic effects of radiation. Preclinical data indicate that amifostine could reduce the risk of secondary cancers caused by radiation and certain forms of chemotherapy.
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PMID:Radioprotectants: pharmacology and clinical applications of amifostine. 979 95

Administered before cytotoxic chemotherapy or radiation, the aminothiol, amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA), provides broad-spectrum cytoprotection of various normal tissues without attenuating antitumor response. The basis for the selectivity of action resides in the anabolism of amifostine at the normal tissue site by membrane-bound alkaline phosphatase. Dephosphorylation to the free thiol, WR-1065, is followed by rapid uptake into normal tissues. In contrast, uptake into tumor tissue is slow to negligible. Pretreatment with amifostine provides protection of normal tissues from the cytotoxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes, and radiation. Additionally, the mutagenic and carcinogenic effects of these modalities are also attenuated. Preclinical studies show significant protection of marrow progenitor cells. Synergistic effects in marrow recovery are noted with the sequential use of amifostine and granulocyte colony-stimulating factor. Protection of kidneys and neural tissues from cisplatin toxicity has been shown, as well as protection of the heart, intestinal crypt cells, and pulmonary tissues from chemotherapy and radiation, and vasculoconnective and musculoconnective tissue in an irradiated field. Comparative in vitro and in vivo studies using murine and human tumor xenografts show no protection of antitumor effects of these same therapies despite the protection of normal organs. The unique preclinical profile of amifostine serves as the basis for the clinical development program for this new broad-spectrum cytoprotective agent.
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PMID:The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine. 1034 55

Fotemustine (Muphoran, S10036), a nitrosourea derivative active in the treatment of malignant melanoma and primary brain tumors, was evaluated in combination with the free radicals cytoprotective agent amifostine (Ethyol, WR-2721) and its alkaline phosphatase (AP)-generated active metabolite WR-1065 in four human melanoma (RPMI-7950, SK-MEL2, SK-MEL5 and WM-115) and lung fibroblast (MRC-5) cell lines. No difference in AP activity was found among the melanoma cell lines, but AP was found to be significantly higher in MRC-5. For combination experiments, cell lines were first exposed to amifostine or WR-1065 for 15 min and then exposed to fotemustine for two cell doubling times. Non-cytotoxic amifostine and WR-1065 concentrations used (0.2 and 0.6 and 0.1 and 0.3 mmol/l, respectively) were deduced from clinically achieved plasma values. Interactions were analyzed from the variations in IC(50) of fotemustine induced by pre-exposure of the cells to amifostine or WR-1065. In all melanoma cell lines, amifostine enhanced the cytotoxic activity of fotemustine as a significant decrease in IC(50) was observed. No significant difference was found between synergistic effects achieved with amifostine and WR-1065 given at half concentrations. No differential effect was found in the MRC-5 cell line as compared with the melanoma cell lines. Expression variation of O(6)-methylguanine methyltransferase was not found to be implicated in the interaction. The present results demonstrating that amifostine or its main active metabolite do not impair the cytotoxicity of fotemustine justify an extensive clinical evaluation of this combination in metastatic melanoma.
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PMID:Enhancement of fotemustine (Muphoran) cytotoxicity by amifostine in malignant melanoma cell lines. 1190 6

Amifostine (Ethyol), an inorganic thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues that provides cytoprotection against ionizing radiation and chemotherapeutic agents, thus preserving the efficacy of radiotherapy and chemotherapy. This review summarizes the preclinical data and clinical experience with amifostine, and provides insight into future clinical directions. Amifostine, an inactive pro-drug, is transformed to an active thiol after dephosphorylation by alkaline phosphatase found in the normal endothelium. The absence of alkaline phosphatase in the tumoral endothelium and stromal components, and the hypovascularity and acidity of the tumor environment, may explain its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. Intravenous administration of amifostine 740-900 mg/m(2) before chemotherapy and 250-350 mg/m(2) before each radiotherapy fraction are widely used regimens. The US Food and Drug Administration has approved the use of amifostine as a cytoprotector for cisplatin chemotherapy and for radiation-induced xerostomia. Ongoing trials are being conducted to determine the efficacy of amifostine in reducing radiation-induced mucositis and other toxicities. Novel schedules and routes of administration are under investigation, and may further simplify the use of amifostine and considerably broaden its applications.
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PMID:Amifostine in clinical oncology: current use and future applications. 1198 63

Amifostine (Ethyol, WR-2721) is a cytoprotective drug approved by the US Food & Drug Administration for intravenous administration in cancer patients receiving radiation therapy and certain forms of chemotherapy. The primary objective of this project was to develop orally active amifostine nanoparticles using spray drying technique. Two different nanoparticle formulations (Amifostine-PLGA (0.4:1.0 and 1.0:1.0)) were prepared using a Buchi B191 Mini Spray Dryer. A water-in-oil emulsion of amifostine and PLGA (RG 502) was spray dried using an airflow of 600 L h(-1) and input temperature of 55 degrees C. A tissue distribution study in mice was conducted following oral administration of the formulation containing drug-polymer (0.4:1.0). The efficiency of encapsulation was 90% and 100%, respectively, for the two formulations while the median particle sizes were 257 and 240 nm, with 90% confidence between 182 and 417 nm. Since amifostine is metabolized to its active form, WR-1065, by intracellular alkaline phosphatase, the tissue levels of WR-1065 were measured, instead of WR-2721. WR-1065 was detected in significant amounts in all tissues, including bone marrow, jejunum and the kidneys, and there was some degree of selectivity in its distribution in various tissues. This work demonstrates the feasibility of developing an orally effective formulation of amifostine that can be used clinically.
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PMID:Oral delivery of spray dried PLGA/amifostine nanoparticles. 1532 80