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Molecules (Basel, Switzerland) Apr 2008Curative radiation therapy of pelvic malignancies, frequently results in dose limiting toxicities such as serous, mucoid, or more rarely, bloody diarrhea. Several... (Review)
Review
Curative radiation therapy of pelvic malignancies, frequently results in dose limiting toxicities such as serous, mucoid, or more rarely, bloody diarrhea. Several studies have evaluated the cytoprotective effects of amifostine in preventing rectal mucositis associated with radiation treatment. We searched Medline for published comparative studies that evaluated the use of amifostine to reduce radiation-induced toxicity associated with pelvic irradiation. In ten studies there was an evidence-based cytoprotection (P less than 0.05)by amifostine. Although results are variable, current evidence suggests that amifostine may have a radioprotective effect in the rectal mucosa, particularly when administered intrarectally. Significant improvements were seen in both symptomatic and objective(rectosigmoidoscopy) end points. There is a need to conduct well-designed clinical trials with sufficient numbers of participants to confirm these findings together with a cost benefit study. Objective measurements using rectosigmoidoscopy are superior to subjective measures such as WHO or RTOG/EORTC toxicity grading scales.
Topics: Amifostine; Cytoprotection; Endpoint Determination; Humans; Radiation; Rectal Diseases; Treatment Outcome
PubMed: 18463591
DOI: 10.3390/molecules13040892 -
Toxicology Mechanisms and Methods Nov 2023Amifostine is used in chemotherapy and radiotherapy as a cytoprotective adjuvant alongside DNA-binding chemotherapeutic agents. It functions by reducing free radicals...
Amifostine is used in chemotherapy and radiotherapy as a cytoprotective adjuvant alongside DNA-binding chemotherapeutic agents. It functions by reducing free radicals and detoxifying harmful metabolites. Methotrexate, as an antimetabolite drug has been considered for treating various cancers and autoimmune diseases. However, the cytotoxic effects of methotrexate extend beyond tumor cells to crucial organs, including the heart. This study applied the HUVEC cell line as a reference model for researching the characteristics of vascular endothelium and cardiotoxicity. The current study aimed to assess amifostine's potential cytoprotective properties against methotrexate-induced cellular damage. Cytotoxicity was measured using the MTT assay. Apoptotic rates were evaluated by Annexin V-FITC/PI staining flow cytometry. The genoprotective effect of amifostine was determined using the comet assay. Cells were exposed to various amifostine doses (10-200 μg/mL) and methotrexate (2.5 μM) in pretreatment culture condition. Methotrexate at 2.5 μM revealed cytotoxicity, apoptosis, oxidative stress and genotoxicity while highlighting amifostine's cyto/geno protective properties on HUVECs. Amifostine significantly decreased the levels of ROS and LPO while preserving the status of GSH and SOD activity. Furthermore, it inhibited genotoxicity (tail length, %DNA in tail, and tail moment) in the comet assay. Amifostine markedly attenuated methotrexate-induced apoptotic cell death (early and late apoptotic rates). These findings convey that amifostine can operate as a cytoprotectant agent.
Topics: Humans; Amifostine; Methotrexate; Human Umbilical Vein Endothelial Cells; Antineoplastic Agents; Oxidative Stress; DNA
PubMed: 37537746
DOI: 10.1080/15376516.2023.2238069 -
Bulletin Du Cancer Sep 1996Originally developed against the effects of ionizing radiations, amifostine is an organic thiophosphate compound shown able to selectively protect normal tissues against... (Clinical Trial)
Clinical Trial Randomized Controlled Trial Review
Originally developed against the effects of ionizing radiations, amifostine is an organic thiophosphate compound shown able to selectively protect normal tissues against cytotoxic agents in cellular and animal models, without protecting tumor tissues. Amifostine is a prodrug which is dephosphorylated into its active metabolite, a free thiol derivative, by membrane alkaline phosphatase of the target issue. This unique metabolism supports its cellular selectivity and its preferential uptake by normal tissues. In phase II clinical trials, a decreased toxicity has been demonstrated in patients given alkylating agents; however, reduction of the response has not been observed. On the basis of these results, a prospective, randomized, phase III study has been conducted in patients with ovarian carcinoma receiving a combination of cisplatinum and cyclophosphamide. A significant decrease in hematologic, renal and neurologic toxicity was observed in the amifostine-treated patients compared with the control group, and response rates did not significantly differ between the two groups. Insufficient or emerging data are only available for other applications, including either in vitro manipulation of hematopoietic grafts or in vivo treatment of non-Hodgkin's lymphoma, head and neck carcinoma, non-small cell lung cancer and radioprotection. No data are yet available in regard to the potential protective effects of amifostine against mutagenicity and cancerogenicity of both chemo- and radiotherapy.
Topics: Amifostine; Animals; Antineoplastic Agents; Bone Marrow; Disease Models, Animal; Drug Tolerance; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Kidney; Neoplasms; Neoplasms, Experimental; Prospective Studies; Radiation Injuries; Radiation-Protective Agents; Radiotherapy
PubMed: 8952658
DOI: No ID Found -
Chemical Senses Jan 2021Taste buds in the oral cavity have a complex immune system regulating normal functions and inflammatory reactions. Cyclophosphamide (CYP), a chemotherapy drug, has...
Taste buds in the oral cavity have a complex immune system regulating normal functions and inflammatory reactions. Cyclophosphamide (CYP), a chemotherapy drug, has wide-ranging disruptive effects on the taste system including loss of taste function, taste sensory cells, and capacity for taste cell renewal. In bladder epithelium, CYP also induces inflammation. To determine if CYP induces inflammation in taste buds, we used immunohistochemistry to examine tumor necrosis factor alpha (TNF-α) (a proinflammatory cytokine) expression over a 72-hour period. Expression of TNF-α increased in a subset of PLCβ2 labeled (Type II) cells, but not SNAP-25 labeled (Type III) cells, between 8 and 24 h postinjection and declined slowly thereafter. This inflammatory response may play an important role in the disruptive effects of CYP on the taste system. Further, pretreatment with amifostine, a sulfhydryl drug known to protect normal tissues during chemo- or radiation therapy, reduced the amount of CYP-induced TNF-α expression in taste buds, suggesting this drug is capable of protecting normal cells of the taste system from adverse effects of CYP. Amifostine, used as a pretreatment to CYP and possibly other chemotherapy drugs, may offer clinical support for preventing negative side effects of chemotherapy on the taste system.
Topics: Amifostine; Cyclophosphamide; Cytoprotection; Humans; Inflammation; Taste Buds
PubMed: 34161570
DOI: 10.1093/chemse/bjab031 -
Seminars in Oncology Dec 2004While concurrent chemoradiotherapy is a standard treatment for good-performance patients with non-small cell lung cancer, acute esophagitis is a frequent toxicity. The... (Clinical Trial)
Clinical Trial Randomized Controlled Trial Review
Randomized phase II study of amifostine mucosal protection by either subcutaneous injection or rapid IV bolus for patients with inoperable stage II-IIIA/B or stage IV non-small cell lung cancer with oligometastases receiving concurrent radiochemotherapy with carboplatin and paclitaxel followed by...
While concurrent chemoradiotherapy is a standard treatment for good-performance patients with non-small cell lung cancer, acute esophagitis is a frequent toxicity. The incidence of severe acute esophagitis > or = grade 3 in patients treated with standard (once-daily) radiation therapy alone is 1.3%, increasing to 14% to 25% with the addition of concurrent chemotherapy, and 24% to 34% for the combination of hyperfractionated (twice-daily) radiation therapy plus concomitant chemotherapy. Although esophagitis is almost never a cause of mortality, it results in significant morbidity and may force treatment breaks, which are associated with inferior outcome in non-small cell lung cancer. Substantial investigative efforts to prevent or ameliorate esophagitis have been conducted. We describe herein the rationale/study design for a multi-institutional, phase II randomized study to evaluate either daily subcutaneous or intravenous bolus infusions of amifostine in patients with non-small cell lung cancer who receive standard fractionated thoracic radiation therapy concurrently with weekly paclitaxel and carboplatin chemotherapy.
Topics: Amifostine; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Combined Modality Therapy; Follow-Up Studies; Humans; Injections, Subcutaneous; Lung Neoplasms; Mucous Membrane; Radiation-Protective Agents
PubMed: 15726523
DOI: 10.1053/j.seminoncol.2004.12.012 -
Seminars in Oncology Aug 1996To determine the efficacy of pretreatment with amifostine in diminishing the hematologic and nonhematologic toxicities of cyclophosphamide and cisplatin in previously... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
To determine the efficacy of pretreatment with amifostine in diminishing the hematologic and nonhematologic toxicities of cyclophosphamide and cisplatin in previously untreated patients with stage III/IV ovarian cancer, a multicenter randomized controlled trial of cyclophosphamide (1,000 mg/m(2)) and cisplatin (100 mg/m(2) with or without amifostine (910 mg/m(2)) was performed. Two hundred forty-two patients with stage III/IV epithelial ovarian cancer were enrolled. Following primary surgery, patients were stratified and randomized to either cyclophosphamide/cisplatin (CP; 120 patients) or amifostine plus CP (122 patients) every 3 weeks for six cycles. Patient characteristics were similar in both groups. Cytoprotective end points and tumor response were evaluated, including the need to delay or discontinue therapy because of toxicity and the incidence of febrile neutropenia with associated complications. Fourteen patients treated with CP discontinued protocol therapy because of hematologic or renal toxicity (eight hematologic and six renal). In contrast, only one patient treated with amifostine plus CP discontinued protocol therapy for hematologic or renal toxicity (P < .001). Forty-three percent of CP patients compared with 22% of amifostine plus CP patients had grade 4 neutropenia (P = .001); total days in hospital were reduced from 258 in the CP arm to 11 in the amifostine plus CP arm (P = .009, two-sided). Sixty-five percent of the CP patients and 41% of the amifostine plus CP patients (P = .004) had the next cycle of CP delayed because of an absolute neutrophil count below 1,500/microL at day 22. Platelet and red blood cell transfusion support were substantially reduced in the group that received amifostine. The serum creatinine failed to return to < or = to 1.5 mg/dL by day 22, requiring a delay in chemotherapy in 15% and 5%, respectively, of the CP and amifostine plus CP groups (P = .014). Over the six cycles, the incidence and severity of peripheral neuropathy were also significantly reduced in the amifostine-treated group (P = .029). Pathologic response rates and survival curves were equivalent. The significant reduction in the CP-induced acute and cumulative hematologic, renal, and neurologic toxicities by amifostine pretreatment with equivalent response and survival indicates selective cytoprotection. This selective effect has the potential to affect quality of life and medical economic considerations.
Topics: Amifostine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cisplatin; Cyclophosphamide; Female; Humans; Kidney; Neoplasm Staging; Ovarian Neoplasms; Peripheral Nervous System; Premedication; Survival Analysis; Treatment Outcome
PubMed: 8783673
DOI: No ID Found -
Seminars in Oncology Apr 1999High-dose chemotherapy with autologous stem cell transplantation is an increasingly used procedure in oncohematologic diseases and represents a promising strategy in... (Review)
Review
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.
Topics: Amifostine; Animals; Bone Marrow Purging; Bone Marrow Transplantation; Clinical Trials as Topic; Cytoprotection; Drug Evaluation, Preclinical; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Protective Agents; Transplantation Conditioning; Transplantation, Autologous
PubMed: 10348263
DOI: No ID Found -
Luminescence : the Journal of... Feb 2015The aim of this present work is to investigate the interaction between amifostine and human serum albumin (HSA) in simulated physiological conditions by spectroscopic...
The aim of this present work is to investigate the interaction between amifostine and human serum albumin (HSA) in simulated physiological conditions by spectroscopic methods to reveal potential toxic effects of the drug. The results reflected that amifostine caused fluorescence quenching of HSA through a static quenching process, which was further confirmed by the electrochemical experiments. The binding constants at 290, 297 and 304 K were obtained as 2.53 × 10(5) /M, 8.13 × 10(4) /M and 3.59 × 10(4) /M, respectively. There may be one binding site of amifostine on HSA. The thermodynamic parameters indicated that the interaction between amifostine and HSA was driven mainly by hydrogen bonding and electrostatic forces. Synchronous fluorescence spectra, circular dichroism and Fourier transform infrared spectroscopy results showed amifostine binding slightly changed the conformation of HSA with secondary structural content changes. Förster resonance energy transfer study revealed high possibility of energy transfer with amifostine-Trp-214 distance of 3.48 nm. The results of the present study may provide valuable information for studying the distribution, toxicological and pharmacological mechanisms of amifostine in vivo.
Topics: Amifostine; Binding Sites; Electrochemical Techniques; Fluorescence; Humans; Serum Albumin; Thermodynamics
PubMed: 24962599
DOI: 10.1002/bio.2693 -
Tumori 1999Much 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... (Review)
Review
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.
Topics: Amifostine; Animals; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Humans; Radiation-Protective Agents; Radiotherapy; Tumor Cells, Cultured
PubMed: 10363072
DOI: No ID Found -
Radiologic Technology 1999
Topics: Amifostine; Humans; Neoplasms; Radiation-Protective Agents
PubMed: 10432542
DOI: No ID Found