Comparison of uroprotective efficacy of mesna and amifostine in Cyclophosphamide- induced hemorrhagic cystitis in rats.
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BACKGROUND: Hemorrhagic cystitis (HC) is a dose limiting side effect of cyclophosphamide (CYP). AIM: In this study, we aimed to investigate the role of amifostine in the protection of CYP-induced HC and compare its efficacy with mesna. SETTING AND DESIGN: This animal study was conducted in the Experimental Animals Breeding and Research Center of the Medical Faculty of Uludag University. MATERIALS AND METHODS: Male Wistar rats (150-200 g; 10 rats per group) were randomly assigned to four groups. Group I (control group) received no drugs, group II received CYP (200 mg/kg, i.p.) alone, group III received amifostine (200 mg/kg, i.p.) and CYP, and group IV received CYP and mesna (40 mg/kg, i.p.) immediately and 4 and 8 h after administration of CYP. Bladders of animals were assessed macroscopically and histologically 24 h later. Gross assessment for presence of edema and hemorrhage and histological evaluation of damage to the bladder were scored according to Gray's criteria. STATISTICAL ANALYSIS USED: For macroscopic and microscopic data, we used statistical evaluation by Kruskal-Wallis nonparametric analysis of variance followed by the Mann-Whitney U-test. RESULTS: All the animals in group II had evidence of HC. Significant histological damage and macroscopic changes were present in this group compared to control group (P<0.001). The median scores for bladder damage in group III and IV were significantly lower compared to group II (P<0.001). When the median scores for bladder damage of group I, III, and IV were compared, there was no significant difference among these groups. CONCLUSION: This study demonstrated the efficacy of amifostine in prevention of cyclophosphamide-induced hemorrhagic cystitis. (+info)
Radiotherapy alone, versus radiotherapy with amifostine 3 times weekly, versus radiotherapy with amifostine 5 times weekly: A prospective randomized study in squamous cell head and neck cancer.
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BACKGROUND: The main objective of this study was to investigate whether nondaily intravenous administration of amifostine was as effective as daily intravenous administration with regard to the reduction of the incidence of Grade 2 or greater xerostomia in patients with head and neck cancer. METHODS: Ninety-one patients who received bilateral irradiation for head and neck cancer were included. Thirty patients received no amifostine (AMI-0), 31 patients received amifostine at a dose of 200 mg/m2 3 times weekly (AMI-3), and 30 patients received amifostine at a dose of 200 mg/m2 daily (5 times weekly) (AMI-5). Acute and late xerostomia and quality of life (QOL) were assessed at baseline, 6 weeks later, and at 6-month intervals from 6 months to 24 months postradiotherapy. RESULTS: Grade 2 or greater late xerostomia differed significantly at 6 months (AMI-0 74% vs. AMI-3 67% vs. AMI-5 52%; P = .03), but not thereafter. During follow-up, patient-rated xerostomia deteriorated more in AMI-0 patients (mean difference score:, 52 for AMI-0 compared with 25 for AMI-3, and 29 for AMI-5; P = .01). Nausea and emesis were reported most frequently as side effect, but Grade 2 or greater toxicity was observed in only 4 patients. However, 28% of patients discontinued amifostine before the end of radiotherapy. CONCLUSIONS: Long-term, patient-rated xerostomia was less for the AMI-3 and AMI-5 groups through 2-year follow-up, but no difference was noted between the AMI-3 and AMI-5 groups. For late xerostomia according to the Radiation Therapy Oncology Group criteria, the same effect was observed at 6 months, but not thereafter. (+info)
Individualization of the subcutaneous amifostine dose during hypofractionated / accelerated radiotherapy.
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BACKGROUND: Individualization of the daily dose of amifostine may prove of value in achieving maximum cytoprotection during radiotherapy. PATIENTS AND METHODS: Using an algorithm based on: i) the gradual increase of the amifostine dose, ii) an amifostine tolerance-recording scale and iii) the intermittent administration of dexamethasone, the individualization of the subcutaneous amifostine dose was prospectively attempted in a large cohort of 132 cancer patients, treated with 12-15 consecutive fractions of 3.4-3.5 Gy (hypofractionated accelerated radiotherapy with cytoprotection, HypoARC). RESULTS: Using the above algorithm, a daily dose of 1000 mg of amifostine was successfully delivered in 62% of patients. An additional 20% of patients tolerated well a mean daily dose of 750-975 mg. Nausea and fatigue were minimal, while fever/rash enforced amifostine interruption in 7% of cases. CONCLUSION: Individualization of the amifostine dose allowed an up to two-fold increased daily-dose administration of amifostine and can be tested as a support to aggressive radio-chemotherapy schemes aiming at improving the cure rates of cancer patients, while avoiding excess toxicity. (+info)
Zebrafish as a "biosensor"? Effects of ionizing radiation and amifostine on embryonic viability and development.
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The zebrafish (Danio rerio) has emerged as a popular vertebrate model system for cancer and treatment-related research. Benefits include ease of care, rapid development, optical clarity of embryos, which allows visualization of major organ systems, and opportunities for genetic manipulation. However, specific parameters of radiation sensitivity have not been systematically documented. We investigated the effects of radiation and a radiomodifier on zebrafish viability and embryonic development. Embryos were exposed to gamma-radiation (5, 10, or 20 Gy) at sequential times postfertilization and serially assessed for viability and morphologic abnormalities. As expected, lethality and morphologic perturbations were more pronounced earlier in embryogenesis and with higher radiation doses and were partially reversed by amifostine. The effects of radiation and concurrent treatment with amifostine on the developmental organization of the eye and brain were striking. Radiation resulted in hypocellularity and disorganization of the cellular layers of the retina, effects partially reversed by amifostine, as well as lens opacification. Radiation strikingly reduced the volume of brain, but the volume loss was substantially blocked by amifostine. Increased terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling signal was noted in both the irradiated eye and brain, but reduced by amifostine. Finally, irradiating embryos resulted in caspase activation detectable in 96-well microplates, which was proportional to the number of embryos and radiation dose; the degree of activation was markedly reduced by amifostine. These results together suggest the power and versatility of the zebrafish in assessing the effects of radiation and radiomodifiers on organ and tissue development. (+info)
Amifostine improves hemodynamic parameters in doxorubicin-pretreated rabbits.
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Amifostine reduces nephrotoxicity and myelotoxicity of alkylating agents. Little is known about its role in preventing cardiotoxicity. We studied if amifostine could affect the hemodynamic parameters in doxorubicin-pretreated rabbits. The animals were divided into six groups consisting of 6 rabbits each. Group 1--doxorubicin iv 2 mg/kg of body weight 4 times every 14 days (cumulative dose 8 mg/kg); group 2--a dose of doxorubicin was 3 mg/kg (cumulative dose 12 mg/kg); groups 3 and 4--amifostine iv 30 mg/kg 15 min prior to doxorubicin 2 and 3 mg/kg, respectively, groups 5 and 6--amifostine- and physiological saline-treated controls. Two-three weeks after the last dose the animals were anesthetized and cardiac index (CI) i.e. cardiac output/body weight, and total peripheral resistance (TPR) were calculated using the method of human I(125) albumin dilution. Mean CI was 71.4 +/- 40.5 ml/min/kg in group 2, 135.8 +/- 41.2 in group 5 (p < 0.001), and 116.4 +/- 47.8 in group 6 (p < 0.001), TPR was 4.7 +/- 3.3 kPa x s/l, 1.1 +/- 1.2 (p < 0.001), and 1.9 +/- 1.1 (p < 0.001), respectively. In group 4, CI was 135.4 +/- 33.2, and TPR was 1.1 +/- 0.6. The differences in CI and TPR between groups 2 and 4 were statistically significant (p < 0.001). In conclusion, pretreatment with doxorubicin at the total dose of 12 mg/kg significantly reduced CI and increased TPR. Amifostine improved CI and TPR in doxorubicin-pretreated rabbits. (+info)
Amifostine: the first selective-target and broad-spectrum radioprotector.
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After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been shown to specifically protect normal tissues from damage caused by radiation and chemotherapy. An inactive prodrug, amifostine is converted to an active thiol by dephosphorylation by alkaline phosphatase in the normal endothelium. The hypovascularity and acidity of the tumor environment and the differential expression of alkaline phosphatase in normal and neoplastic tissues contribute to its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free-radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug Administration has approved the i.v. use of amifostine to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Nonetheless, amifostine has potential applications in many other oncologic settings. Novel schedules and routes of administration are under investigation and may further simplify the use of amifostine, reduce any undesired effects, and considerably broaden its applications. This review summarizes the clinical experience with amifostine and provides insight into future clinical directions. (+info)
Influence of amifostine on late radiation-toxicity in head and neck cancer--a follow-up study.
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AIM: The late toxicities due to multimodal therapy of advanced head and neck cancers were analysed. The impact of cytoprotection with amifostine is the specific objective of this report. PATIENTS AND METHODS: A total of 851 patients (717 men, 134 women) with head and neck cancer were included in this prospective study. Of these patients, 519/851 had received amifostine before radio(chemo)therapy, while 332 control patients had not received any kind of cytoprotection before irradiation. Primary radiochemotherapy was performed in 282 patients and adjuvant radiation was administered in 569. The follow-up examination was carried out at our outpatient department 21.4 months (median, range 2.3 to 149 months) after the primary therapy. RESULTS: Late xerostomia was seen in 765/851 patients (89.9%). Altered taste was reported by 284/851 (33.5%). These symptoms were reduced significantly by amifostine. No influence was seen on interstitial lymph edema (48.4%), or stenosis of the cervical esophagus (20.4%). Secondary symptoms such as dysphagia (78.8%) also had a trend for reduction. CONCLUSION: The administration of amifostine offers an opportunity to reduce selected long-term toxicities for survivors of head and neck cancer. (+info)
Relationship between phosphorylated histone H2AX formation and cell survival in human microvascular endothelial cells (HMEC) as a function of ionizing radiation exposure in the presence or absence of thiol-containing drugs.
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Human microvascular endothelial cells (HMEC) were exposed to ionizing radiation at doses ranging from 0 to 16 Gy in either the presence or absence of the active thiol forms of amifostine (WR1065), phosphonol (WR255591), N-acetyl-l-cysteine (NAC), captopril or mesna. Each of these clinically relevant thiols, administered to HMEC at a dose of 4 mM for 30 min prior to irradiation, is known to exhibit antioxidant properties. The purpose of this investigation was to determine the relationship(s), if any, between the frequency of radiation-induced histone H2AX phosphorylation at serine 139 (gamma-H2AX) in cells and subsequent survival, as assessed by colony-forming ability, in exposed cell populations as a function of the presence or absence of each of the five thiol compounds during irradiation. gamma-H2AX formation in irradiated cells, as a function of relative DNA content, was quantified by bivariant flow cytometry analysis with FITC-conjugated gamma-H2AX antibody and nuclear DAPI staining. gamma-H2AX formation in cells was measured as the relative fold increase as a function of the treatment conditions. The frequency of gamma-H2AX-positive cells increased with increasing dose of radiation followed by a dose- and time-dependent decay. The most robust response for gamma-H2AX formation occurred 1 h after irradiation with their relative frequencies decreasing as a function of time 4 and 24 h later. To assess the effects of the various thiols on gamma-H2AX formation, all measurements were made 1 h after irradiation. WR1065 was not only effective in protecting HMEC against gamma-H2AX formation across the entire dose range of radiation exposures used, but it was also significantly more cytoprotective than either its prodrug (WR2721) or disulfide (WR33278) analogue. WR1065 had no significant effect on gamma-H2AX formation when administered immediately or up to 30 min after radiation exposure. An inhibitory effect against gamma-H2AX formation induced by 8 Gy of radiation was expressed by each of the thiols tested. NAC, captopril and mesna were equally effective in reducing the frequency of gamma-H2AX formation, with both WR1065 and WR255591 exhibiting a slightly more robust protective effect. Each of the five thiols was effective in reducing the frequency of gamma-H2AX-positive cells across all phases of the cell cycle. In contrast to the relative ability of each of these thiols to inhibit gamma-H2AX formation after irradiation, NAC, captopril and mesna afforded no protection to HMEC as determined using a colony-forming survival assay. Only WR1065 and WR255591 were effective in reducing the frequencies of radiation-induced gamma-H2AX-positive cells as well as protecting against cell death. These results suggest that the use of gamma-H2AX as a biomarker for screening the efficacy of novel antioxidant radioprotective compounds is highly problematic since their formation and disappearance may be linked to processes beyond simply the formation and repair of radiation-induced DSBs. (+info)