Effect Of Amifostine Research Articles

Amifostine for salivary glands in high-dose radioactive iodine treated differentiated thyroid cancer.

Radioactive iodine treatment for differentiated thyroid cancer possibly results in xerostomia. Amifostine has been used to prevent the effects of irradiation to salivary glands. To date, the effects of amifostine on salivary glands in radioactive iodine treated differentiated thyroid cancer remain uncertain. To assess the effects of amifostine on salivary glands in high-dose radioactive iodine treated differentiated thyroid cancer. Studies were obtained from computerized searches of MEDLINE, EMBASE, The Cochrane Library and paper collections of conferences held in Chinese. Randomised controlled clinical trials and quasi-randomised controlled clinical trials comparing the effects of amifostine on salivary glands after radioactive iodine treatment for differentiated thyroid cancer with placebo and a duration of follow up of at least three months. Two authors independently assessed risk of bias and extracted data. Two trials with 130 patients (67 and 63 patients randomised to intervention versus control) were included. Both studies had a low risk of bias. Amifostine versus placebo showed no statistically significant differences in the incidence of xerostomia (130 patients, two studies), the decrease of scintigraphically measured uptake of technetium-99m by salivary or submandibular glands at twelve months (80 patients, one study), and the reduction of blood pressure (130 patients, two studies). Two patients in one study collapsed after initiation of amifostine therapy and had to be treated by withdrawing the infusion and volume substitution. Both patients recovered without sequelae. Meta-analysis was not performed on the function of salivary glands measured by technetium-99m scintigraphy at three months after high dose radioactive iodine treatment due to the highly inconsistent findings across studies (I(2) statistic 99%). None of the included trials investigated death from any cause, morbidity, health-related quality of life or costs. Results from two randomised controlled clinical trials suggest that the amifostine has no significant radioprotective effects on salivary glands in high-dose radioactive iodine treated differentiated thyroid cancer patients. Moreover, no health-related quality of life and other patient-oriented outcomes were evaluated in the two included trials. Randomised controlled clinical trials with low risk of bias investigating patient-oriented outcomes are needed to guide treatment choice.

Analysis of the cytoprotective effect of amifostine on the irradiated inner ear of guinea pigs: an experimental study

A radiacao pode causar lesao na orelha interna podendo provocar surdez sensorio-neural e inclusive levar a anacusia. A amifostina e uma substância citoprotetora seletiva de tecidos sadios, amplamente utilizada durante a radio e quimioterapia de tumores malignos. OBJETIVO: O objetivo deste estudo experimental foi verificar se existe efeito antioxidante e radioprotetor da amifostina no orgao de Corti de cobaias albinas irradiadas em regiao de cabeca e pescoco. MATERIAL E METODO: O estudo realizado envolveu quatro grupos de animais: um grupo foi submetido a irradiacao em dose unica de 350cGy. Dois grupos receberam a mesma dose de radiacao, porem receberam doses de 100 e 200mg/kg de amifostina, 30 minutos antes da irradiacao. Um grupo recebeu apenas amifostina, na dose de 200mg/Kg. Todas as cobaias foram sacrificadas 30 dias apos o experimento e suas bulas retiradas para estudo em microscopio de varredura. RESULTADO: O grau de lesao das celulas ciliadas externas foi menor nos dois grupos que receberam a amifostina que no grupo apenas irradiado. Nao foi encontrada diferenca de protecao entre os grupos que receberam doses de 100 e 200mg/kg de amifostina. Nao houve lesao no grupo que recebeu apenas amifostina. CONCLUSAO: Amifostina mostrou ser um radioprotetor do orgao de Corti de cobaias albinas irradiadas.

Analysis of the Cytoprotective Effect of Amifostine on the Irradiated Inner Ear of Guinea Pigs: An Experimental Study

SummaryRadiation can cause damage to the inner ear, from a simple hearing loss all the way to profound deafness. Amifostine is a cytoprotective substance extensively used during radio-chemotherapy for malignant tumors.Aimthe objective of the present investigation was to establish the antioxidant and radioprotective effects of amifostine on the organ of Corti of albino guinea pigs irradiated in the head and neck region.Materials and MethodsAn experimental study conducted on four groups of guinea pigs were used; One group received only amifostine, one group was submitted to a single dose of 350 cGy and the other two were similarly irradiated but received amifostine doses of 100 or 200 mg/kg. All animals were slaughtered 30 days after the experiment, their bullae were removed and the damaged outer hair cells were counted.ResultThe extent of injury was lower in the outer hair cells of the two groups treated with amifostine compared to the group that was only irradiated. There was no difference between the group treated with 100 and 200 mg/kg of amifostine. The group that received only amifostine had no cochlear damage.ConclusionAmifostine is an effective cytoprotective substance in the Organ of Corti of irradiated guinea pigs.

Amifostine protection against induced DNA damage in γ‐irradiated Escherichia coli cells depend on recN DNA repair gene product activity

Amifostine is the most effective radioprotector known and the only one accepted for clinical use in cancer radiotherapy. In this work, the antigenotoxic effect of amifostine against gamma-rays was studied in Escherichia coli cells deficient in DNA damage repair activities. Assays of irradiated cells treated with amifostine showed that the drug reduced the genotoxicity induced by radiation in E. coli wild-type genotypes and in uvr, recF, recB, recB-recC-recF mutant strains, but not in recN defective cells. Thus, the mechanism of DNA protection by amifostine against gamma-radiation-induced genotoxicity appears to involve participation of the RecN protein that facilitates repair of DNA double-strand breaks. The results are discussed in relation to amifostine's chemopreventive potential.

Protective Effects of Amifostine and Cyclooxygenase-1 Inhibitor against Normal Human Epidermal Keratinocyte Toxicity Induced by Methotrexate and 5-Fluorouracil

Our study aimed to find more effective protective agents against mucosa toxicity induced by methotrexate and 5-fluorouracil. We focused on the relationship between oral mucositis and keratinocyte injury and examined methotrexate and 5-fluorouracil-induced cytotoxicity in normal human epidermal keratinocyte cell lines. Cell viability and superoxide radical activity were measured based on converting WST-1 (4-[3-(4-indophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzen disulfonate) to a water-soluble formazan dye. DNA synthesis by 5-bromo-2'-deoxyuridine incorporation was measured as an indirect parameter of cell proliferation. Allopurinol and amifostine were used as the radical scavengers. l-glutamine was used as a mucosa-protective agent. A cyclooxygenase inhibitor interrupting the production of hydroxyl radicals in the arachidonic acid cascade was also examined. 5-fluorouracil and methotrexate caused cytotoxicity due to the activation of intracellular superoxide radicals specifically on normal human epidermal keratinocytes. From the electron spin resonance study, it was found that allopurinol was a superoxide radical scavenger, while amifostine was hydroxyl radical scavenger. Allopurinol showed no effect on the cytotoxicity due to 5-fluorouracil and methotrexate. The cell injury induced by methotrexate was restored by amifostine. However, the cell injury induced by 5-fluorouracil was markedly recovered by a selective cyclooxygenase-1 inhibitor compared to amifostine. It was suggested that amifostine and cyclooxygenase-1 inhibitor could be useful protective agents against methotrexate and 5-fluorouracil chemotherapeutic toxicity. Additionally, this in vitro cell injury model using normal human epidermal keratinocytes may be useful for understanding the pathophysiology of oral mucositis induced by chemotherapeutic agents.

The role of amifostine in the treatment of head and neck cancer with cisplatin-radiotherapy

Although head and neck cancer is not one of the most common cancers, it is a debilitating disease with poor prognosis and considerable post-treatment normal tissue toxicity. The unremitting search to increase the therapeutic ratio between tumour control and late normal tissue injury led to the adoption of altered fractionation schedules. While the increase in acute toxicity can be managed with appropriate medical support, damage produced to late responding tissues is usually irreversible, therefore clinically unacceptable. By altering the conventionally fractionated radiotherapy both loco-regional control and overall survival are increased. Moreover, phase III randomized trials indicated that the combined administration of cisplatin and radiotherapy further improves treatment outcome. Although the uptake of cisplatin in normal cells is not amplified by the combined modality treatment, cisplatin, by itself is a highly cytotoxic agent. Therefore, the need for normal tissue protection has arisen. Amifostine is a selective, radio-protective drug used in both radiotherapy and chemotherapy to reduce normal tissue toxicity. This paper provides an overview of clinical trials employing cisplatin-radiotherapy treatment for advanced head and neck cancer with specific focus on normal tissue toxicity. The emerging role of radioprotectors and furthermore, the effectiveness of amifostine in combined cisplatin-radiotherapy trials are presented.

Cytoprotective effects of amifostine in the treatment of childhood malignancies

Multi-systemic acute side effects occur, in response to intensive therapies that have been applied in childhood malignancies in recent years. Amifostine has rarely been used in the childhood cancers as a multisystemic protective agent for minimizing these side effects. In this study, the effectiveness of amifostine in combination with chemotherapy for childhood cancer treatment has been researched. Of 11 subjects (2.5 months-17 years) 4 subjects had leukemia, 4 had solid tumor, and 3 had lymphoma. For these 11 subjects, 29 chemotherapy courses were given in combination with amifostine, and 20 without amifostine. Their hematological, gastrointestinal and hepatic toxicity were evaluated according to the WHO toxicity criteria. Amifostine was given intravenously in a dose of 740 mg/m(2), one to three consecutive days depending on the chemotherapy regimen. The hemoglobin, leukocyte, and platelet levels of the two groups were not statistically different. However, when comparing the courses of the patients receiving the same medications at the same doses, in the group with amifostine, mean erythrocyte transfusion requirement was significantly reduced (P = 0.025). In 31% of the courses with amifostine and 50% of the courses without amifostine, febrile neutropenia developed. Gastrointestinal system and hepatic toxicity was significantly reduced in the courses with amifostine with respect to those without it (P = 0.001). Vomiting, hypotension and nausea were the only side effects related to amifostine. Use of amifostine during the treatment of childhood cancers with intensive chemotherapy and/or radiotherapy significantly reduced the erythrocyte transfusion requirements of the patients as well as gastrointestinal and hepatic toxicity.

Amifostine, a Radioprotectant Agent, Protects Rat Hepatic Microsomal Membranes Against Ionizing Radiation Induced Damage

In the present study, the protective effect of amifostine (WR-2721), which is the only approved radioprotective agent by the Food and Drug Administration (FDA), was investigated against the deleterious effects of ionizing radiation on rat liver microsomal membranes at molecular level. To achieve this, Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated using Cobalt-60 irradiator at a single dose of 800 cGy, decapitated after 24 h and the microsomal membranes isolated from the livers of these rats were analyzed using FTIR spectroscopy. The results revealed that ionizing radiation caused a significant increase in the concentration of lipids whereas amifostine treatment restored the lipid content of microsomal membranes to control values. In addition, the significant increase in lipid order and a significant decrease in membrane dynamics resulting from ionizing radiation were prevented by amifostine. While ionizing radiation caused a significant decrease in the lipid to protein ratio, amifostine injection before radiation, maintained this ratio as in the control group. Furthermore, ionizing radiation-induced variations in protein secondary structure were restored by amifostine. In conclusion, the data obtained in this study indicate that amifostine administration to the rats prior to whole body irradiation protects liver microsomal membranes against the radiation induced damages. Supported by TUBITAK, (SBAG-2939) and by the METU (BAP-2006-07-02-0001).

The role of amifostine on late normal tissue damage induced by pelvic radiotherapy with concomitant gemcitabine: an in vivo study

In this in vivo study, we aimed to assess the radioprotective effect of amifostine on late normal tissue damage induced by gemcitabine concomitant with pelvic radiotherapy by histopathological and quantitative methods. Fifty-six male Wistar albino rats were randomly divided into seven experimental groups as follows: (I) gemcitabine, (II) radiation + gemcitabine, (III) radiation + gemcitabine + amifostine, (IV) radiation + amifostine, (V) sham radiation, (VI) amifostine, (VII) radiation. Irradiation was given to pelvic region with a dose of 25 Gy in 5 fractions. Amifostine was given for 30 min; gemcitabine was administered 24 h before the first fraction of radiotherapy. All animals were killed at the end of 4th month. Pathological examination was performed and the tissue collagen content was measured in bladder and rectal tissues. Fifty-one animals that were alive at the end of the follow-up period were analyzed. Thirty-five animals (68.6%) revealed grades I-III late effect in histopathological examination. We observed grade III colitis in 1 animal (radiation + gemcitabine) and bladder fibrosis in 4 animals (radiation and radiation + gemcitabine groups). There was no significant difference between any groups for bladder cystitis and fibrosis by Kruskal-Wallis method. Colitis was seen significantly lower in the radiation + gemcitabine + amifostine group (P = 0.0005). The collagen contents in the bladder and rectum of radiation and radiation + gemcitabine groups were markedly increased as compared to the sham group. This effect was reversed in the groups which received amifostine in addition to radiation and radiation + gemcitabine groups, but this difference was not significant. This study demonstrated that amifostine may have a beneficial effect in limiting rectal colitis from the radiosensitizing effect of gemcitabine.

Amifostine reduces lung vascular permeability via suppression of inflammatory signalling

Despite an encouraging outcome of antioxidant therapy in animal models of acute lung injury, effective antioxidant agents for clinical application remain to be developed. The present study investigated the effect of pre-treatment with amifostine, a thiol antioxidant compound, on lung endothelial barrier dysfunction induced by Gram-negative bacteria wall-lipopolysaccharide (LPS). Endothelial permeability was monitored by changes in transendothelial electrical resistance. Cytoskeletal remodelling and reactive oxygen species (ROS) production was examined by immunofluorescence. Cell signalling was assessed by Western blot. Measurements of Evans blue extravasation, cell count and protein content in bronchoalveolar lavage fluid were used as in vivo parameters of lung vascular permeability. Hydrogen peroxide, LPS and interleukin-6 caused cytoskeletal reorganisation and increased permeability in the pulmonary endothelial cells, reflecting endothelial barrier dysfunction. These disruptive effects were inhibited by pre-treatment with amifostine and linked to the amifostine-mediated abrogation of ROS production and redox-sensitive signalling cascades, including p38, extracellular signal regulated kinase 1/2, mitogen-activated protein kinases and the nuclear factor-kappaB pathway. In vivo, concurrent amifostine administration inhibited LPS-induced oxidative stress and p38 mitogen-activated protein kinase activation, which was associated with reduced vascular leak and neutrophil recruitment to the lungs. The present study demonstrates, for the first time, protective effects of amifostine against lipopolysaccharide-induced lung vascular leak in vitro and in animal models of lipopolysaccharide-induced acute lung injury.

Effect of Preliminary Amifostine Administration in Irradiation of Parotid Glands

To investigate the effect of amifostine, we administered amifostine, a radioprotective agent, 30 minutes before exposing the maxillary region of mice, including the parotid gland, to 5 Gy or 10 Gy X-ray irradiation. The survival rate was recorded, and changes in the parotid gland morphology were investigated by examining the hematoxylin and eosin (HE)-stained specimens and light microscope autoradiography (LMARG) images obtained 30 days after irradiation. A survival rate of 100% was not observed in any group administered 200 mg/kg amifostine with or without irradiation. Among the groups irradiated with 10 Gy X-rays, the survival rate was higher and the survival period was longer in the 100 mg/kg amifostine group than in the no amifostine group. The histological findings in the group that received 5 Gy irradiation without amifostine were as follows : auxetic growth of acinar cells, nuclei of all sizes, cells in the mitotic phase, and cells undergoing apoptosis. Further, the treated groups were compared with the no amifostine and no irradiation group (untreated control). LMRG imaging revealed that the number of reduced silver grains per mm2 of acinar cells after 30 min of 3H-leucine administration was higher than that after 120 min in mice treated with 100 mg/kg amifostine with or without 5 Gy irradiation. This observation was similar to that in the untreated control.This finding suggests that although amifostine administration reduces the adverse effects of irradiation on the parotid gland, higher doses of amifostine may be fatal.

Radiation Effects and Radioprotection in MC3T3-E1 Mouse Calvarial Osteoblastic Cells

Little is known about the mechanisms and treatment of radiation-induced inhibition of craniofacial bone growth. In an earlier study, the radioprotector amifostine (WR-2721) administered to rabbits before irradiation radioprotected cultured orbitozygomatic complex periosteal osteoblast-like cells. This study assessed the effects of amifostine and its active metabolite on the radiation survival, function, and phenotype of mouse calvarial osteoblast-like cells in a cell culture model. MC3T3-E1 newborn mouse calvarial osteoblast-like cells underwent gamma-radiation (0 to 10 Gy) in the presence or absence of either WR-2721 or WR-1065, its active metabolite (10 to 10 M). The effects of radiation with and without drugs were assessed using endpoints of colony-forming ability, cell viability, alkaline phosphatase activity, and expression of osteoblastic phenotype genes (alkaline phosphatase, collagen type I, osteocalcin, and osteopontin). All experiments were replicated at least in triplicate. Irradiation resulted in a dose-dependent inhibition of clonogenic cell survival. Pretreatment with WR-1065, but not WR-2721, resulted in a significant improvement of osteoblast-like cell survival. Specifically, maximum radioprotection was observed with 10 M WR-1065 at a clinically relevant 2-Gy dose of irradiation. No significant radioprotection was observed at the lower (5 x 10 M) concentration of WR-1065. Furthermore, radiation seemed to suppress the expression of osteoblastic phenotype-related genes in a dose-dependent manner. This study reveals improved survival after irradiation in osteoblast-like cells treated with WR-1065 in vitro and corroborates previous findings from animal models. Further studies using this agent and similar drugs are important for devising strategies to prevent radiation-induced inhibition of craniofacial bone growth.

Amifostine Protection Against Mitomycin-induced Chromosomal Breakage in Fanconi Anaemia Lymphocytes

Fanconi anaemia (FA) is a rare genetic chromosomal instability syndrome caused by impairment of DNA repair and reactive oxygen species (ROS) imbalance. This disease is also related to bone marrow failure and cancer. Treatment of these complications with radiation and alkylating agents may enhance chromosomal breakage. We have evaluated the effect of amifostine (AMF) on basal and mitomycin C (MMC)-induced chromosomal breakage in FA blood cells using the micronucleus assay. The basal micronuclei count was higher among FA patients than healthy subjects. Pre-treatment with AMF significantly inhibited micronucleation induced by MMC in healthy subjects (23.4 ± 4.0 – MMC vs 12.3 ± 2.9 – AMF → MMC) MN/1000CB, p < 0.01, one way ANOVA) as well as in FA patients (80.0 ± 5.8 – MMC vs 40.1 ± 5.8 – AMF → MMC) MN/1000CB, p < 0.01, ANOVA). Release of ROS by peripheral blood mononuclear cells treated with AMF → MMC and measured by chemoluminometry showed that AMF-protection was statistically higher among FA patients than in healthy individuals. Based on these results we suggest that AMF prevents chromosomal breakage induced by MMC, probably by its antioxidant effect.

The effect of amifostine or IMRT to preserve the parotid function after radiotherapy of the head and neck region measured by quantitative salivary gland scintigraphy

Purpose In this retrospective study, two approaches to preserve the parotid function after radiotherapy (RT) were compared: application of the radioprotective agent amifostine during RT and parotid-sparing intensity-modulated radiotherapy (IMRT). Patients and methods Patients were qualified for this analysis if (1) both parotid glands received a radiation dose of ⩾50 Gy using conventional radiotherapy techniques (cRT) or if they received a parotid-sparing IMRT as alternative, if (2) salivary gland scintigraphies before and after RT were performed, and if (3) a normal parotid function was present before RT. Quantitative salivary gland scintigraphy was used to assess the parotid gland function. Results Altogether 275 salivary gland scintigraphies of 100 patients were analyzed. The mean relative tracer uptake (Δ U) of patients treated with cRT, cRT with amifostine and IMRT 1–12 months after RT was 0.59 (95%CI 0.54–0.65), 0.67 (95%CI 0.59–0.76), and 0.93 (95%CI 0.78–1.07), respectively. The mean relative Δ U 13–47 months after RT was 0.40 (95%CI 0.32–0.49), 0.60 (95%CI 0.48–0.71), and 0.92 (95%CI 0.56–1.28). At 1–12 months after RT, ANOVA testing with post-hoc comparison using the Bonferroni correction showed a significant difference between IMRT and cRT ( p < 0.001) or IMRT and amifostine ( p < 0.01). The difference between amifostine and cRT was not significant during the first year. At 13–47 months after RT, the difference between cRT and amifostine was significant ( p = 0.02). Conclusion Our data suggest that both amifostine and IMRT are able to partially preserve the parotid function after radiotherapy. The effect of IMRT appeared to be much greater.

Amifostine Use in Radiation-Induced Kidney Damage

PURPOSE To assess the degree of protective effects of amifostine on kidney functions via semiquantitative static renal scintigraphy and histopathologic analysis. MATERIAL AND METHODS 30 female albino rats were divided into three equal groups as control (CL), radiotherapy alone (RT), and radiotherapy + amifostine (RT+AMI). The animals in the CL and RT groups were given phosphate-buffered saline, whereas the animals in the RT+AMI group received amifostine (200 mg/kg) by intraperitoneal injection 30 min before irradiation. RT and RT+AMI groups were irradiated with a single dose of 6 Gy using a (60)Co unit at a source-skin distance of 80 cm to the whole right kidney. They were followed up for 6 months. CL, RT, and RT+AMI groups underwent static kidney scintigraphy at the beginning of the experiment and, again, on the day before sacrificing. Histopathologically, tubular atrophy and fibrosis of the kidney damage were evaluated. RESULTS After irradiation, the median value of right kidney function was 48% (44-49%) and 50.5% (49%-52%) in RT and RT+AMI groups, respectively (p = 0.0002). Grade 1 kidney fibrosis was observed to be 60% in the RT group, while it was only 30% in the RT+AMI group. Grade 2 kidney fibrosis was 30% and 0% in the RT and RT+AMI group, respectively. Grade 1 tubular atrophy was 70% and 50% in the RT and RT+AMI group, respectively. Grade 2 tubular atrophy effect was the same in both groups (10%). CONCLUSION Static kidney scintigraphy represents an objective and reproducible method to noninvasively investigate kidney function following irradiation. Amifostine produced a significant reduction in radiation-induced loss of renal function.

Cytoprotective Efficacy of Amifostine Against Radiation- Induced Rectal Toxicity: Objective and Subjective Grading Scales for Radiomucositis

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<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.

Limited Cytoprotective Effects of Amifostine in High-Dose Radioactive Iodine 131–Treated Well-Differentiated Thyroid Cancer Patients: Analysis of Quantitative Salivary Scan

The aim of present study was to investigate the cytoprotective effect of amifostine on salivary glands in 131I-treated differentiated thyroid cancer (DTC) patients using serial quantitative analysis of salivary gland scans. Serial quantitative salivary scintigraphies were performed in 80 newly diagnosed DTC patients (9 men, 71 women; mean age, 43.2 years old; range, 21-58 years old). Forty-two patients were assigned randomly to the amifostine treatment group, which received 300 mg/m2 amifostine intravenously before 131I administration. In both amifostine-treated and nontreated groups statistically significant declines of functional parameters after 131I treatment were revealed by quantitative salivary scintigraphy in DTC patients. Amifostine pretreatment did not prevent the parenchymal damage to major salivary gland function after 131I treatment (F = 1.37, p = 0.2461). However, the dose of 131I had significant effects on salivary gland function after 131I treatment (F = 9.72, p = 0.0002). The present study did not show cytoprotective effects of amifostine for DTC patients treated with 131I.

Comparison of the protective effects of melatonin and amifostine on radiation-induced epiphyseal injury

Purpose: We compared the effects of amifostine and melatonin in preventing radiation-induced epiphyseal growth plate injury in rats.Materials and methods: Four-week-old (65–85 g), growing male Sprague-Dawley rats were randomly assigned to receive radiation alone, at 25 Gy in three fractions (group R), or this dose of fractionated radiation proceeded by prophylactic amifostine 200 mg/kg i.p. (group A), melatonin 15 mg/kg i.p. (group M), or amifostine + melatonin (group AM). The right rear extremity of each animal was irradiated while the contralateral leg was shielded from radiation, as a control. Bone growth based on the length of the tibia, femur, and overall limb was calculated 6 weeks after the treatment.Results: In groups R, A, M, and AM, the mean growth loss (GL) for the overall limb was 56.9 ± 8.1%, 46.8 ± 7.7%, 36.6 ± 4.3%, and 38.5 ± 5.1%, respectively. The limb length discrepancies (LLD) in groups R, A, M, and AM were 13.8 ± 1.4%, 10.5 ± 0.3%, 7.4 ± 0.7%, and 8.8 ± 1.1%, respectively. Differences in LLD were significant between each treatment group and group R (range: p = 0.0001–0.001). Differences in either of mean GL and LLD were not significant between groups M and AM; however both of these groups had significantly less GL and LLD than group A.Conclusions: We observed a superior radioprotective function of melatonin over amifostine in preventing radiation-induced epiphyseal growth plate injury, without any increase in radioprotective effect by adding amifostine to melatonin.

Incidence of tissue toxicities in gamma ray and fission neutron-exposed mice treated with Amifostine

Purpose: To determine the effects of Amifostine or WR-151327 on the incidence of lethal and non-lethal toxicities in a large cohort of mice exposed to γ-ray or fission-spectrum neutron radiation.Methods: To analyze data from 4000 B6CF1 mice which received a single whole body irradiation (WBI) with 206 cGy or 417 cGy cobalt-60 gamma rays or 10 cGy or 40 cGy of fission-spectrum neutrons (average energy 0.85 MeV) produced by the Janus reactor at Argonne National Laboratory. In the neutron cohort, Amifostine, WR-151327, saline or nothing was injected once, intraperitoneally, 30 minutes before irradiation. In the cobalt-60 cohort, WR-151327 was omitted from the same protocol. At the time of natural death, tissue toxicities found in these mice were recorded, and these records were analyzed. While all previous studies focused on the modulation of life shortening effects of WBI by Amifostine, in this study we calculated changes in the frequencies of 59 tissue toxicities and changes in the total number of toxicities per animal.Results: Amifostine protected against specific non-tumor pathological complications (67% of the non-tumor toxicities induced by gamma irradiation, 31% of the neutron induced specific toxicities), as well as specific tumors (56% of the tumor toxicities induced by gamma irradiation, 25% of the neutron induced tumors). Amifostine also reduced the total number of toxicities per animal for both genders in the gamma ray exposed mice and in males in the neutron exposed mice.Conclusions: Amifostine was protective against many, but not all, tissue toxicities caused by WBI gamma and neutron irradiation.

Effects of Amifostine on Acute and Late Toxicity of Radiotherapy and Concurrent Chemotherapy for Local Advanced Non-Small Cell Lung Cancer

Effects of Amifostine on Acute and Late Toxicity of Radiotherapy and Concurrent Chemotherapy for Local Advanced Non-Small Cell Lung Cancer