Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We showed previously that amifostine (WR 2721; Ethyol), a protector against carboplatin-induced toxicities, changed the pharmacokinetics of carboplatin in tumor-bearing nude mice. In the present study, the influence of amifostine on the pharmacokinetics of carboplatin was studied in patients when carboplatin was given in combination with three doses of amifostine, administered just before the carboplatin infusion and 2-4 h thereafter. Compared with a control group of patients who received carboplatin alone, the patients receiving the combination had a longer final half-life of ultrafilterable platinum species [5.0 h versus 3.5 h in patients with a normal creatinine clearance (Clcr > 80 ml/min); 5.6 h versus 4.2 h in those with an impaired renal function (50 < Clcr < 80 ml/min)]. This might be caused by an influence of amifostine on the renal clearance of carboplatin as suggested by a transient increase in serum creatinine levels 24 h after treatment in the patients receiving the combination (mean +/- SD: 34.1% +/- 17.2% versus -1.8% +/- 16.5% in patients treated with carboplatin alone). The impact of these changes on the area under the concentration-time curves of the ultrafilterable platinum species was hardly noticeable in patients with a normal renal function but led to a significant increase in patients with an impaired renal function (395 +/- 59 micromol/l.h versus 280 +/- 62 micromol/l.h in patients receiving carboplatin alone). The clinical relevance of this influence is unclear, although theoretically it may result in an increase in the efficacy of carboplatin, as has been observed in tumor-bearing nude mice.
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PMID:Pharmacokinetics of carboplatin with and without amifostine in patients with solid tumors. 981 38

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

In addition to the cytoprotective benefits of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) to normal cells, it also prevents the induction of somatic mutations that can lead to therapy-induced second cancers. The mutagenic effects of cyclophosphamide, an agent that is known to be mutagenic to normal cells, were determined in mouse splenocytes using a mutational assay system. Cyclophosphamide 100 mg/kg increased mutant frequencies 10-fold. In contrast, amifostine 100 mg/kg, whether administered 30 minutes before or 2 hours after cyclophosphamide administration, resulted in eightfold lowered mutant frequencies. To address potential cytoprotective effects on tumors exposed to this dose, amifostine was administered to tumor-bearing mice either 30 minutes before or 2 hours after the administration of cyclophosphamide. Cyclophosphamide (range, 10 to 100 mg/kg) was administered intraperitoneally into mice 4 days following the injection of 3.5 x 10(5) viable fibrosarcoma (FSa) cells. At this time, microcolonies of FSa tumors containing 50 to 200 cells were present in the lung. The number of FSa lung nodules formed at the end of 14 days in control animals was compared with that of animals treated with cyclophosphamide +/- amifostine. No cytoprotection of murine FSa tumors by amifostine was observed across the entire cyclophosphamide dose range tested, regardless of time of administration, demonstrating the utility of amifostine as a chemopreventive drug under conditions that do not allow cytoprotection for tumor cells.
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PMID:Chemopreventive doses of amifostine confer no cytoprotection to tumor nodules growing in the lungs of mice treated with cyclophosphamide. 1034 56

High-dose chemotherapy with autologous stem cell transplantation is an increasingly used procedure in oncohematologic diseases and represents a promising strategy in selected patients with solid tumors. In autologous stem cell transplantation, the risk of reinfusion of clonogenic tumor cells is a remarkable biologic obstacle that can be at least partly overcome by ex vivo graft purging to reduce residual tumor. Mafosfamide and 4-hydroxyperoxycyclophosphamide, active metabolites of cyclophosphamide, are the most widely used pharmacologic agents for ex vivo bone marrow purging. However, in addition to killing tumor cells, they are toxic to normal bone marrow as measured by reduced colony-forming unit granulocyte-macrophage (CFU-GM). Thus, the therapeutic index of these alkylating agents is narrow, and parameters for dose selection must include toxicity to normal bone marrow progenitor cells that can delay bone marrow engraftment and increase risk of infections, bleeding complications, hospitalization, and the need for a costly transplantation procedure. Amifostine (WR-2771, Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) selectively protects human CFU-GM progenitor cells from the cytotoxicities of active metabolites of cyclophosphamide without altering its cytotoxic effect on malignant cells. This has been demonstrated both in preclinical and clinical studies in patients with breast cancer, malignant lymphomas, and acute leukemia. Amifostine use during the ex vivo procedure significantly shortened the time to bone marrow engraftment with decreased incidence of infections and need for red blood cell transfusions.
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PMID:Ex vivo manipulation of hematopoietic stem cells for transplantation: the potential role of amifostine. 1034 63

Amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) is a thiophosphate cytoprotectant agent with the potential to abrogate many chemotherapy-induced toxicities. In preclinical studies, amifostine protected against the cytotoxic effects of alkylating agents, platinum analogs, and radiation therapy in normal tissues, but preserved antineoplastic activity of these therapeutic modalities in tumor tissue. Most normal tissues were protected, including bone marrow, kidney, lung, and peripheral nerves. Recently, the protective effects of amifostine were confirmed by clinical studies, including a randomized trial demonstrating protection from cisplatin-induced myelosuppression, nephrotoxicity, and neurotoxicity. Many common chemotherapeutic agents, such as cisplatin, paclitaxel, and vinca alkaloids, cause dose-limiting neurotoxicity. Therefore, a neurologic protectant may help to reduce toxicity to patients, improve the tolerability of combination therapy with multiple neurotoxic agents, or allow investigators to intensify chemotherapy dose. This report reviews the potential role of amifostine as a neuroprotectant. Future clinical trials may expand the use of amifostine to abrogate neurotoxicity from multiple agents and combinations and compare amifostine with other neuroprotective agents.
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PMID:Neurologic protection by amifostine. 1034 65

Effective radiotherapy for patients with cancer should include maximal tumor cell killing with minimal injury to normal tissue. However, current radiation doses that can be delivered without causing severe damage to surrounding normal tissues are often insufficient to eradicate a tumor. Recently, a number of agents have been developed to protect normal tissue from the harmful effects of antitumor therapies. The aminothiol amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) has been the subject of extensive research as a prospective protector. While this drug has been approved for use to reduce toxicities associated with cisplatin, several studies also have demonstrated that amifostine protects normal tissues from both acute and late radiation damage without protecting the tumor. Consequently, higher radiation doses could be used with less than or equal risk to surrounding normal tissues. This report reviews the physicochemical basis of radiation therapy on biologic tissues and the mechanisms responsible for the cytoprotective effects of amifostine. The increasing body of biochemical, preclinical, and clinical data could justify the use of protectors such as amifostine with radiotherapy to provide improved therapeutic efficacy and quality of life for the patient.
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PMID:Radioprotective effects of amifostine. 1034 66

Although chemotherapeutic regimens remain limited in activity against non-small cell lung cancer, some novel cytotoxic agents and radiotherapy techniques, alone or in combination, have shown promising advances. Numerous clinical trials have demonstrated increases in overall response rates, and some agents have shown additive or synergistic effects against tumor tissue. The cytoprotectant amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) is being assessed for its protection of normal tissue against the toxic effects of chemotherapy and radiotherapy and for its potential role in enhancing the efficacy of these modalities. Protection from dose-limiting toxicities may allow dose escalation and improve the therapeutic index. Current and future investigations of novel agents and modalities, with or without cytoprotectants, should lead to better prognosis and prolonged survival rates.
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PMID:Future directions in non-small cell lung cancer. 1034 70

The chemoprotective effect of amifostine (WR2721) was studied in a BDIX rat model with intracerebral BT4C glioma implants. Twenty-one rats were given cisplatin 5 mg/kg i.p., 21 were given amifostine 200 mg/kg i.p. + cisplatin 5 mg/kg i.p. Ten rats served as untreated controls. An immunohistochemical method for analysis of cisplatin-DNA adducts was used to elucidate the adduct formation in tumor, normal brain and kidney. Tumor volume and serum creatinine level were analysed 10 days after treatment. In animals pretreated with amifostine there was a delayed adduct formation rate in the normal brain, and in the kidney cortex the number of tubular cells with extremely high adduct level was reduced. No difference in adduct formation was seen in tumors. Tumor volume was significantly larger following amifostine + cisplatin (66% of controls) compared to cisplatin alone (38% of controls). Weight loss was, however, severe in rats given cisplatin alone. In the tumor growth study only 3 out of 11 rats treated with cisplatin 5 mg/kg alone survived until time of sacrifice at 10 days, whereas all those pretreated with amifostine survived. Mean serum creatinine was 48 micromol/l (controls), 146 micromol/l (cisplatin) and 59 micromol/l (amifostine + cisplatin). A marked reduction of histopathological renal changes was found when amifostine was added. Amifostine thus significantly reduced general and renal toxicity of cisplatin. The tumor growth retardation was stronger when cisplatin was given alone but this is probably related to general toxicity and malnutrition indirectly supported by the fact that amifostine did not significantly reduce cisplatin-DNA adduct formation in tumors. The results of the present study suggest that amifostine may have a role in increasing the therapeutic ratio of cisplatin, also in the treatment of malignant glioma.
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PMID:Effects of amifostine on cisplatin induced DNA adduct formation and toxicity in malignant glioma and normal tissues in rat. 1036 Apr 75

Much effort is being made to reduce the iatrogenic toxicity of antineoplastic treatments in order to improve the quality of life of cancer patients. Cytoprotection of healthy tissue by thiol group donors is one of the most promising lines of research. Amifostine is the most extensively studied drug in the category. We reviewed the extensive medical literature on amifostine. The protective effect of amifostine has been demonstrated for cisplatin-induced toxicity in lung and ovarian cancer, with particular regard to nephrotoxicity, neurotoxicity and neutropenia. No protective effect has been seen for tumor cells owing to a selective action of amifostine on healthy tissues. A frequent side effect of amifostine is a transient decreases in blood pressure; it is usually asymptomatic if an easily handled premedication is given. Cytoprotection by amifostine is also well known for alkylating drugs and radiation therapy, whereas it is still the object of study for new drugs, especially taxanes. The present work also includes a cost-benefit analysis and a prospective view on the most promising research lines.
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PMID:Protection of normal tissues from radiation and cytotoxic therapy: the development of amifostine. 1036 72

Ex vivo pharmacological purging of bone marrow has been used to eliminate clonogenic tumor cells contaminating the autograft and potentially responsible of relapse. A considerable improvement of pharmacological purging would be achieved only if normal marrow progenitor cells could be selectively protected by the cytotoxicity of these agents. Amifostine (WR-2721; Ethyol), a phosphorylated aminothiol compound, has been shown to have this property both in vivo and in vitro. We describe here, an experimental model for ex vivo purging of peripheral blood progenitor cell (PBPC) collections based on the combination of 3 mg/ml of amifostine and the alkylating agent nitrogen mustard. Amifostine pretreatment resulted in a statistically significant protection of normal late and early progenitor cells. Under the same experimental conditions, we observed a 4-6 log reduction of contaminating leukemic cells (i.e., K-562 and CEM) and in contrast to the protection of normal peripheral blood progenitor cells, preincubation of contaminating K-562 or CEM with amifostine did not significantly alter the LD95 nitrogen mustard concentration. Moreover, when we tested fresh human leukemia progenitor cells, amifostine pretreatment sensitized the leukemic cells to the cytotoxic effects of NM.
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PMID:Ex vivo pharmacological purging of leukapheresis collections with nitrogen mustard: amifostine pretreatment improves both early and late peripheral blood progenitor cell recovery. 1051 97


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