Radioprotective Effects Of Amifostine Research Articles

Radioprotective Effects of Amifostine, L-Carnitine and Vitamin E in Preventing Early Salivary Gland Injury due to Radioactive Iodine Treatment.

Standard treatment of differentiated thyroid cancer includes total thyroidectomy and high-dose Radioactive Iodine Therapy (RIT) for ablation of remnant thyroid tissue. When administered systemically, RIT can cause radiation-induced damage in non-targeted normal tissues. The aim of the present study was to compare the protective effects of amifostine (AMI), LCarnitine (LC), and Vitamin E (EVIT) against high dose radioactive iodine treatment induced Salivary Gland (SG) damage using SG scintigraphy and histopathological examination. Forty adult guinea pigs were studied. Twenty guinea pigs receive 555-660 MBq 131Iodine intraperitoneally (IP) to ablate the thyroid and impair the parenchymal function of the SGs. The animals were divided into eight groups as follows: (1) Group 1 (control): 1 mL IP PS (physiological saline); (2) Group 2: single dose of 200 mg/kg IP AMI one hour prior to 1 mL IP PS; (3) Group 3: 200 mg/kg IP LC and 1 mL IP PS for 10 days; (4) Group 4: 40 mg/kg intramuscular (IM) EVITand 1 mL IP PS for 10 days; (5) Group 5: IP RIT after premedication; (6) Group 6: Single dose of 200 mg/kg IP AMI one hour prior to RIT and IP RIT after premedication; (7) Group 7: IP RIT after premedication and 200 mg/kg IP LC for 10 days starting one day before RIT; and (8) Group 8: IP RIT after premedication and 40 mg/kg IM EVIT for 10 days starting one day before RIT. Scintigraphy was performed 1 month after treatment. SGs were examined by light microscopy and a histopathological scoring system was used to assess the degree of SG damage. There were significant differences in the body weight and thyroid hormone levels between the groups after treatment. The individual use of AMI, LC and EVIT for radioprotection yield different levels of protection against radioactive iodine treatment injury in SGs; however, none of the agents could provide absolute protection at the doses administered in this experimental model.

Examination of the effect of ovarian radiation injury induced by hysterosalpingography on ovarian proliferating cell nuclear antigen and the radioprotective effect of amifostine: an experimental study.

AimThe aim of this study was to examine the effect of amifostine on cellular injury in the ovarian tissue induced by hysterosalpingography (HSG).MethodsIn total, forty 4-month old female Wistar Albino rats were assigned into 8 groups. Each group contained 5 rats. Group 1 (G1): rats were decapitated without any procedure. Group 2 (G2): rats were decapitated after 3 hours of total body irradiation. Group 3 (G3): rats were decapitated 3 hours after HSG procedure. Group 4 (G4): rats were decapitated 3 hours after HSG procedure performed 30 min after receiving amifostine 200 mg/kg intraperitoneally. Group 5 (G5): rats were decapitated after 1 month without any procedure. Group 6 (G6): rats were decapitated after 1 month of total body irradiation. Group 7 (G7): rats were decapitated 1 month after HSG procedure. Group 8 (G8): rats were decapitated 1 month after HSG procedure performed 30 min after receiving amifostine 200 mg/kg intraperitoneally. After rats were decapitated under general anesthesia in all groups, blood samples were obtained and bilateral ovaries were removed. One of the ovaries was placed in 10% formaldehyde solution for histological germinal epithelial degeneration, apoptosis and proliferating cell nuclear antigen scoring. The other ovary and blood sera were stored at −80°C. TNF-α, total antioxidant status, total oxidant status, and malondialdehyde levels were studied in tissue samples and anti-mullerian hormone levels in blood samples.ResultsAt the end of the first month, there was significant ovarian germinal epithelium degeneration. Proliferating cell nuclear antigen immunoreactivity was significantly reduced in all other groups when compared with G1 and G5.ConclusionIn conclusion, amifostine could significantly reduce the ovarian cellular injury induced by HSG.

Effect of Amifostine on Sperm DNA Fragmentation and Testes after Radioiodine Treatment.

IntroductionRadioactive iodine (RAI) is commonly used for the treatment of hyperthyroidism caused by Graves’ disease or thyroid nodules. However, information available on the impact of RAI therapy on male gonadal function is scarce. This study aimed to determine any possible damage to testicular tissue and sperm quality caused by RAI therapy, and the radioprotective effect of amifostine against such damage.Material and MethodsIn total, 36 rats were randomly allocated to three groups, including a control group, RAI group (111 MBq Iodine-131), and RAI + amifostine group (111 MBq Iodine-131 and a single dose of 200 mg/kg amifostine). Blood and epididymal sperm samples were taken for hormone analyses and the evaluation of spermatological parameters. The TUNEL assay and haematoxylin-eosin were used to stain testicular tissue samples to detect histological changes and apoptosis.ResultsThe groups differed insignificantly for the testicular mass index and spermatozoa concentration. However, spermatozoa motility and percentage of viable spermatozoa were higher in the RAI + amifostine group, compared to the RAI group. Sperm DNA fragmentation and the index of apoptotic germ cells significantly decreased in the amifostine group, in comparison to the radioiodine group. While the testosterone levels showed no significant change, the follicle stimulating hormone (FSH) levels significantly decreased in the RAI + amifostine group.ConclusionAll histopathological parameters and some spermatological parameters showed that RAI therapy caused statistically significant damage of testicular tissue and this damage was reduced by amifostine.

Radioprotective Effects of Amifostine and Lycopene on Human Peripheral Blood Lymphocytes In Vitro

BackgroundRadiation protection is a pivotal challenge for radiation workers employed in medical fields, industry, and also space professionals with an increasing role in medical diagnostic and therapeutic applications. Radioprotective effects of amifostine and lycopene and their ability to moderate the level of radiation-induced chromosomal aberrations were investigated using the dicentric chromosome assay. MethodsParallel human whole blood samples, pretreated with amifostine (250 μg/mL), lycopene (5 μg/mL), and/or their combinations were irradiated for 30 minutes with 60Co γ rays (1, 2, 3, and 4 Gy) with a dose rate of 98.46 cGy/min at SAD = 100 cm, in vitro and cocultured with control groups. The frequencies of chromosomal aberrations in the lymphocyte of the cells were analyzed. ResultsThere were no apparent chromosome aberrations in controls and also in the drug-treated groups in the absence of radiation. Radiodrug treatment significantly decreased frequency of the radiation-induced chromosome aberrations compared with radiation alone (P < .05). Amifostine reduced the frequency of radiation-induced dicentrics by 15.8%, 21.9%, 4.5%, and 11.6%, with dose protection factors (DPFs) of 1.2 ± 0.02, 1.3 ± 0.1, 1.05 ± 0.03, and 1.13 ± 0.02. Lycopene reduced the frequency by 17.2%, 3.07%, 1.63%, and 16.6%, with DPFs of 1.21 ± 0.12, 1.03±0.05, 1.02±0.03 and 1.12±0.03. The combination treatment reduced the frequency by 28%, 24.9%, 9%, and 31.2%, with DPFs of 1.38 ± 0.06, 1.33 ± 0.06, 1.09 ± 0.02, and 1.45 ± 0.03 with radiation doses of 1, 2, 3, and 4 Gy, respectively. ConclusionsIt can be suggested that pretreatment with combined amifostine and lycopene may reduce the extent of ionizing radiation damage in cells.

A Phase I Clinical and Pharmacology Study Using Amifostine as a Radioprotector in Dose-escalated Whole Liver Radiation Therapy

Diffuse intrahepatic tumors are difficult to control. Whole-liver radiotherapy has been limited by toxicity, most notably radiation-induced liver disease. Amifostine is a prodrug free-radical scavenger that selectively protects normal tissues and, in a preclinical model of intrahepatic cancer, systemic amifostine reduced normal liver radiation damage without compromising tumor effect. We hypothesized that amifostine would permit escalation of whole-liver radiation dose to potentially control microscopic disease. We also aimed to characterize the pharmacokinetics of amifostine and its active metabolite WR-1065 to optimize timing of radiotherapy. We conducted a radiation dose-escalation trial for patients with diffuse, intrahepatic cancer treated with whole-liver radiation and intravenous amifostine. Radiation dose was assigned using the time-to-event continual reassessment method. A companion pharmacokinetic study was performed. Twenty-three patients were treated, with a maximum dose of 40 Gy. Using a logistical regression model, compared with our previously treated patients, amifostine increased liver tolerance by 3.3 ± 1.1 Gy (p = 0.007) (approximately 10%) with similar response rates. Peak concentrations of WR-1065 were 25 μM with an elimination half-life of 1.5 h; these levels are consistent with radioprotective effects of amifostine in patients. These findings demonstrate for the first time that amifostine is a normal liver radioprotector. They further suggest that it may be useful to combine amifostine with fractionated or stereotactic body radiation therapy for patients with focal intrahepatic cancer.

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.

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.

Radioprotective Effects of Amifostine on Acute and Chronic Esophageal Injury in Rodents

This study was performed to evaluate the protective benefit of amifostine against esophageal injury from fractionated radiation in a rodent model. Fractionated or sham esophageal irradiation was administered to Fisher-344 rats for 5 consecutive daily fractions of 9 Gy using 150 kV X-rays. Animals received an intraperitoneal injection of amifostine or placebo 30 min before each fraction. Histopathologic analyses for mucosal thickness, submucosal collagen deposition, activation of macrophages, oxidative stress and expression/activation of integrinalphavbeta6 and transforming growth factor (TGF)-beta were performed 5 days and 10 weeks after irradiation. Pre-RT mean mucosal thickness was 35 microm in both the placebo and the amifostine groups. Five days post-RT, mean mucosal thicknesses were 30 microm in the placebo group versus 37 microm in the amifostine group (p = 0.024). At 10 weeks post-RT, the group receiving amifostine experienced a significant decrease in tunica muscularis damage (p = 0.002), submucosal collagen deposition (p = 0.027), and macrophage accumulation (p = 0.026) when compared with the placebo group. The levels of immunoreactivity for oxidative stress, TGF-beta, and integrinalphavbeta6 were significantly decreased 10 weeks post-RT in the group receiving amifostine treatment compared with placebo group. This study demonstrates that amifostine given before each radiation fraction protects against acute and chronic esophageal injury in a rodent model. Protection of the mucosal epithelium integrity by amifostine prevents integrinalphavbeta6 expression which reduces TGF-beta activation and subsequent development of chronic esophageal injury in this model. Further investigation is necessary to determine the clinical relevance of these findings.

Interaction of amifostine and ionizing radiation on transcriptional patterns of apoptotic genes expressed in human microvascular endothelial cells (HMEC)

Purpose Amifostine is a prodrug that requires dephosphorylation by alkaline phosphatase to become activated. This process occurs rapidly within the bloodstream after its i.v. administration to patients undergoing cancer treatment with selected radiation and chemotherapies. Vascular endothelial cells will, therefore, represent a normal cell system that is among the first to experience the radioprotective effects of this agent. Amifostine's active free thiol WR-1065 was investigated to determine its effect on radiation-induced changes in transcriptional patterns and subsequent apoptosis in human microvascular endothelial cells (HMEC) growing in vitro. Methods and materials Human microvascular endothelial cells were grown to confluency and then exposed to WR-1065 at a concentration of 4 mM for 30 min, radiation doses that ranged from 0 to 6 Gy, and WR-1065 at a concentration of 4 mM for 30 min before exposure to ionizing radiation. Cell survival was assessed by clonogenic assay, cell cycle phase was analyzed by flow cytometry, apoptosis was also assessed by flow cytometry in which Anexin V staining and sub-G1 fraction analysis were applied, and gene expression was analyzed by the Clontech Atlas Human cDNA array to identify synergistic and antagonistic effects as a function of amifostine and radiation exposure conditions with a focus on apoptotic-related factors. Results Exposure of HMEC to 4 mM WR-1065 30 min before irradiation resulted in a protection enhancement factor of 2.0; that is, D O-IRR of 1.25 Gy and D O-IRR+WR of 2.56 Gy. Expression profiling revealed 29 genes that were synergistically activated by the combined action of WR-1065 and ionizing radiation, and an additional 12 genes were synergistically or additively suppressed. In particular, a subset of apoptosis-related genes that included caspases 2, 4, and 9 and different members of the bcl family, along with apoptosis-related receptors, were identified as being significantly affected by the combined treatment of WR-1065 and radiation exposure. In addition, a number of cell cycle–related genes that express cyclins A, G1, G2, and D3 and DNA damage/check point proteins ATM, DNA-PK and RAD23B were also found to be significantly affected. Functional assays of apoptosis were also performed that demonstrated the ability of WR-1065 to protect against radiation-induced apoptosis. Conclusions WR-1065, the active thiol form of amifostine, is an effective radioprotector of HMEC as determined by use of clonogenic and apoptotic assays for cell survival. Expression profiling successfully defined the transcriptional response of HMEC to both WR-1065 and ionizing radiation exposure, either alone or in combination, and demonstrated both synergistic and antagonistic effects on the expression of different cellular genes, along with corresponding functional responses. The radioprotective effects of amifostine are not limited to its well-characterized physiochemical properties, which include free-radical scavenging, auto-oxidation leading to intracellular hypoxia, and chemical repair by hydrogen atom donation, but include its ability to modulate the complex transcriptional regulation of genes that are involved in apoptosis, cell cycle, and DNA repair.

Acute toxicity and radioprotective effects of amifostine (WR-2721) or cystamine in single whole body fission neutrons irradiated rats

The radioprotective substances amifostine (WR-2721) and cystamine were tested in rats following their parenteral administration (i.p., i.m., and i.v.). Cystamine is more toxic than amifostine in mice as well as in rats. Amifostine was less toxic after intravenous injection. The radioprotective effects of WR-2721 (160 mg.kg-1) and cystamine (40 mg.kg-1) were not significant when they were administered parenterally 15 - 20 mins before lethal doses of whole body fission neutron irradiation in the thermal column of reactor VVR-S and 30-days lethality served as an integral criterion of postradiation injury to the rat body. The fission neutrons spectrum was characterized by mean energy 0.9-1.0 MeV with 30-40% fluency participation of moderate (E=0.1 MeV) neutrons. The contamination with gamma rays was 22-30 %; the dose rate of whole irradiation was within 0.3 to 0.8 Gy.min-1.

Radioprotective Effects of Amifostine (WR-2721) or Cystamine on Radiation Damage and Its Repair in Rats Whole Body Exposed to Fission Neutrons

Sulphur containing radioprotective drugs amifostine (gammaphos, WR-2721) or cystamine (disulfide of meracaptoethylamine) of Czechoslovak production were examined in whole body fission neutrons irradiated rats in the thermal column of reactor VVR-S. Using the split-dose technic the first sublethal neutron dose in the range 1-2 Gy was followed by second lethal exposures in the two time intervals (3 or 6 days) using whole body fission neutrons irradiations (3 days interval) or whole body gamma-irradiations (6 days interval) for LD50/30 evaluation within next 30 days survival observation. In other experiments the mean survival time (MST) in days was estimated in different rats group, when animals were whole body fission neutrons irradiated twice with 3-days interval using the total lethal doses of 4 or 5 Gy. Protected rats received amifostine (160 mg.kg(-1) i.p. and 200 mg.kg(-1) i.m.) or cystamine (40 mg.kg(-1) i.p. and 50 mg.kg(-1) i.m.), control rats obtained saline 20 min before beginning of irradiation in the amount of 0.5 ml.100 g(-1) of the rat's body weight. Non-significant DRF value 1.13 for WR-2721 i.p. was calculated in survival studies in rats twice neutron irradiated with 3 days interval (DRF 1.04 for cystamine). Chemical protectors were administered before each neutron exposure. MST of twice neutron lethal iradiated rats was prolonged not regularly by radioprotectors tested. WR-2721 and cystamine i.m. were not able to increase 6 days reparation processes after sublethal 2 Gy fission neutrons whole body irradiated rats.

Radioprotective effect of amifostine in radiation pneumonitis

Amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD) is a member of a sulfhydryl-containing class of compounds that protects normal tissue and organs against ionizing radiation damage by scavenging radiation-induced radicals. The goal of this study was to assess the preclinical and clinical data on the protective effect of amifostine in normal organs and tissue. The current literature was reviewed and assessed for progress in the pathogenesis of radiation-induced pulmonary injury. Preclinical and clinical data on the protective effect of amifostine in radiation-induced lung and esophageal injuries were also critically assessed. Significant progress has been made in understanding the pathogenesis of radiation pneumonitis. Preclinical studies have shown strong evidence of the protective effect of amifostine in radiation-induced toxicities in rodents and monkeys. However, available clinical data are not conclusive in showing the protective effect of amifostine in radiation pneumonitis and esophagitis. Amifostine has been well tolerated with a low incidence of toxicities, which included nausea and vomiting (3% to 5%) and transient hypotension during intravenous infusion (7%). Preclinical data are promising for amifostine in protecting thoracic organs from radiation-induced toxicities. Studies measuring the magnitude of gain in tumor control and survival as a result of the enhanced protective effect of amifostine on normal tissue over that of tumor tissue are lacking. Such data would help in designing new approaches to maximize outcome. Additional well-designed phase III studies are necessary to confirm the clinical benefit of amifostine in minimizing radiation- and chemoradiation-related toxicities in patients with lung cancer.

Variable cytotoxicity of amifostine in malignant and non-malignant cell lines

Amifostine is the best known radioprotector and chemoprotector which has already been incorporated into general oncology practice. However, the data regarding its action at the cellular level remain unclear. The present study examined the effect of amifostine with and without ionizing radiation on the growth of malignant and non-malignant cell lines. Amifostine was found to have a remarkable cytotoxic effect on malignant epithelial cell lines but a modest cytotoxic effect on malignant melanoma and non-malignant cell lines. It demonstrated an additive effect with radiation therapy on the malignant cell line and a variable effect on the non-malignant cell line. Endothelial cells were not affected by amifostine, but the myoblast cells showed a synergistic effect of amifostine and radiation. These findings demonstrate that the cytotoxic as well as the radioprotective effect of amifostine are cell-specific. Thus, caution should be exercised in the use of amifostine as a radioprotector, and it should be tested for each model of disease.

150. Multicenter, randomized study assessing the impact of amifostine on normal tissue tolerance during radiotherapy for head and neck cancer

Aim A prospective, randomized multicenter study was conducted to assess toxicity and radioprotective effects of amifostine (EthyolŽ) in head and neck cancer radiotherapy. Assessed were also local control and overall survival. Material and methods Sixty-one patients (43 men and 18 women) from five institutions were randomly assigned to radiotherapy alone (28 patients) or radiotherapy + amifostine (33 patients). Amifostine was given at a dose of 150 mg/m2 15 min prior to each fraction of radiotherapy. Definite and postoperative radiotherapy were given at a total dose of at least 66 Gy (43 patients) or 56 Gy (18 patients), respectively. Acute radiation reactions were assessed using the EORTC/RTOG scale, weekly during radiotherapy, and within 2 weeks afterwards. Late radiation reactions were assessed using SOMA-LENT scale every 3 months for 2 years. Results The side effects of amifostine were generally manageable. In 6 patients amifostine infusion had to be temporarily stopped and in 5 permanently terminated due to hypotension (2 patients), nausea and vomiting (1 patient), septicemia (1 patient) or fever, vertigo and visual disturbances (1 patient). No increase in the frequency of somnolence, nausea/vomiting, sneezing, dizziness, hot flushes, hiccough, shivering, hypocalcemia or allergic reactions was noted. No significant differences in the frequency and degree of radiotherapy-induced mucositis, skin reactions, xerostomia, dysphagia and leucopenia between patients who did and did not receive amifostine were observed during radiotherapy and within the first week after its termination. 2 weeks after termination of radiation musositis was more intensive in the amifostine group (p=0,0449). No significant differences in late radiation reactions were observed. Conclusions The tolerance of amifostine at a dose of 150 mg/m2 is acceptable. No significant impact on acute and late radiation reactions was demonstrated.

Preclinical studies on the radioprotective efficacy and pharmacokinetics of subcutaneously administered amifostine.

The radioprotective effects and pharmacokinetics of subcutaneously (SC) administered amifostine have been investigated in animal studies. Studies in rats using a single dose of amifostine showed that SC administration gave protection from radiation-induced mucositis that is at least equivalent to that achieved by intravenous administration of the drug. These studies also indicate that tissue levels of the active metabolite WR-1065 correlated better with the radioprotective effects of amifostine than do plasma WR-1065 levels. Multiple-dose studies in rats show radioprotective effects equal to or greater than those obtained with intravenous dosing in the setting of fractionated irradiation. In addition, there is no evidence of drug accumulation in either normal or tumor tissue, with tumor WR-1065 levels peaking just above the limits of quantitation during treatment. Preliminary data from studies of SC amifostine in monkeys indicate a plasma pharmacokinetic profile similar to that reported earlier in humans. Tissue WR-1065 levels were higher at 30 minutes after SC dosing than they were after intravenous dosing and were comparable for the two routes at 60 minutes.

Preclinical studies on the radioprotective efficacy and pharmacokinetics of subcutaneously administered amifostine

The radioprotective effects and pharmacokinetics of subcutaneously (SC) administered amifostine have been investigated in animal studies. Studies in rats using a single dose of amifostine showed that SC administration gave protection from radiation-induced mucositis that is at least equivalent to that achieved by intravenous administration of the drug. These studies also indicate that tissue levels of the active metabolite WR-1065 correlated better with the radioprotective effects of amifostine than do plasma WR-1065 levels. Multiple-dose studies in rats show radioprotective effects equal to or greater than those obtained with intravenous dosing in the setting of fractionated irradiation. In addition, there is no evidence of drug accumulation in either normal or tumor tissue, with tumor WR-1065 levels peaking just above the limits of quantitation during treatment. Preliminary data from studies of SC amifostine in monkeys indicate a plasma pharmacokinetic profile similar to that reported earlier in humans. Tissue WR-1065 levels were higher at 30 minutes after SC dosing than they were after intravenous dosing and were comparable for the two routes at 60 minutes. Semin Oncol 29 (suppl 19):2-8. Copyright 2002, Elsevier Science (USA). All rights reserved.

Radioprotective effect of amifostine in patients with head and neck squamous cell carcinoma.

Amifostine (Ethyol; MedImmune Oncology, Gaithersburg, MD) is a radio- and chemoprotective agent currently in clinical use. Based on experimental data showing the potential for mucosal protection and additional information in animal studies showing rapid uptake of amifostine in the salivary glands along with effective radioprotection, several investigators have tested this drug in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The first evidence that amifostine, administered at 200 mg/m(2)/d intravenously before each radiotherapy session, could effectively protect salivary function in patients with HNSCC was provided by McDonald et al in a limited series of HNSCC patients. On the basis of these phase I results, an international multicenter phase III radiotherapy trial with or without amifostine was carried out by Brizel et al in a series of 315 patients with head and neck tumors showing a reduction in xerostomia with no suggestion of tumor protection. Additional data have been obtained in patients with HNSCC regarding the potential protective effect of amifostine on the duration and severity of radio-induced mucositis. This effect was reported in small, randomized studies of patients receiving intensive accelerated radiotherapy (Bourhis et al) or combined radiochemotherapy (Buntzel et al). In conclusion, the experience obtained to date in HNSCC patients treated with radiotherapy supports the selective cytoprotective activity of amifostine to minimize radiation effects while apparently not diminishing tumor control.

Radioprotective effect of amifostine in patients with head and neck squamous cell carcinoma

Amifostine (Ethyol; MedImmune Oncology, Gaithersburg, MD) is a radio- and chemoprotective agent currently in clinical use. Based on experimental data showing the potential for mucosal protection and additional information in animal studies showing rapid uptake of amifostine in the salivary glands along with effective radioprotection, several investigators have tested this drug in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The first evidence that amifostine, administered at 200 mg/m 2/d intravenously before each radiotherapy session, could effectively protect salivary function in patients with HNSCC was provided by McDonald et al in a limited series of HNSCC patients. On the basis of these phase I results, an international multicenter phase III radiotherapy trial with or without amifostine was carried out by Brizel et al in a series of 315 patients with head and neck tumors showing a reduction in xerostomia with no suggestion of tumor protection. Additional data have been obtained in patients with HNSCC regarding the potential protective effect of amifostine on the duration and severity of radio-induced mucositis. This effect was reported in small, randomized studies of patients receiving intensive accelerated radiotherapy (Bourhis et al) or combined radiochemotherapy (Buntzel et al). In conclusion, the experience obtained to date in HNSCC patients treated with radiotherapy supports the selective cytoprotective activity of amifostine to minimize radiation effects while apparently not diminishing tumor control. Semin Oncol 29 (suppl 19):61-62. Copyright 2002, Elsevier Science (USA). All rights reserved.

Effects of amifostine on the proliferation and differentiation of megakaryocytic progenitor cells

This study investigated the effects of amifostine, a clinically usable radioprotector or chemoprotector, on the proliferation and differentiation of normal and X-irradiated cluster of differentiation 34 positive (CD34 +) megakaryocytic progenitor cells (colony-forming unit in megakaryocytes, CFU-Meg) from human placental and umbilical cord blood (CB) in vitro. Amifostine significantly accelerated megakaryocyte colony formation in a plasma clot culture supplemented with recombinant human thrombopoietin because of an increase in immature CFU-Meg-derived large megakaryocyte colony formation. An analysis of the cells that were harvested from the culture showed that amifostine induced a 70- and an 83-fold increase in the total cell and CFU-Meg numbers, respectively, and produced hyperploid megakaryocytes of more than 8 N ploidy. The radioprotective effect of amifostine on the clonal growth of X-irradiated CD34 + CFU-Meg was observed by treatment before or after irradiation. These findings suggest that the action of amifostine extends from immature CFU-Meg to the terminal differentiation of megakaryopoiesis, and its radioprotective effect is shown in megakaryopoiesis and thrombopoiesis.

ASSESSMENT OF THE PROTECTIVE EFFECT OF AMIFOSTINE ON RADIATION-INDUCED PULMONARY TOXICITY

The objective of this study was to assess the radioprotective effects of amifostine in the rat model of radiation-induced lung injury using fractionated doses of radiation, to determine whether amifostine given before irradiation protects tumor from radiation cytotoxicity, and to determine whether changes in plasma levels of transforming growth factor (TGF)- β correlate with radioprotective effect of amifostine. R3230 AC mammary adenocarcinoma was transplanted on the right posterior chest wall of female Fisher-344 rats. Both tumor-bearing and non-tumor-bearing animals were irradiated to the tumor or right lung using 4 MV photons and fractionated dose of 35 Gy/5 fractions/5 days. Animals with tumors and those without were randomized into 4 groups, respectively (8 to 10 rats per group), to receive (1) radiation alone; (2) radiation + amifostine; (3) amifostine alone; (4) sham radiation. Amifostine (150 mg/kg) was given intraperitoneally 30 minutes before each fraction of irradiation. The tumor size was measured twice a week. Breathing rate was assessed every 2 weeks. TGF- β levels in plasma were assessed monthly after treatment. Six months after irradiation, animals were euthanized and lung tissue was processed for hydroxyproline content analysis. A significant increase in breathing frequency started 9 weeks after irradiation in animals that received radiation only. In the radiation + amifostine group, there was both a delay and a significantly lower peak in breathing frequency (P <. 001). Hydroxyproline content was higher in the radiation-alone group than in rats given amifostine prior to radiation (P <. 05). The TGF- β levels in plasma showed an increase from 1 to 3 months after radiation, peaking at 2 months in the rats with (2.80 ± 0.23) or without (5.32 ± 1.21) amifostine compared to sham irradiation. TGF- β levels were significantly lower at 1 to 3 months in rats receiving amifostine plus radiation versus those receiving radiation alone. Tumor growth delay and regrowth rate after radiation were not different between radiation-alone and radiation + amifostine groups. This study confirms the protective effect of amifostine in reducing radiation-induced pulmonary toxicity. No tumor protection was demonstrated after fractionated radiotherapy. The reduction in pulmonary injury with amifostine in paralleling lower plasma levels of TGF- β, suggesting that monitoring plasma levels of this cytokine may reflect the efficacy of an intervention aimed at preventing radiation-induced lung injury.