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Plastic and Reconstructive Surgery Oct 2014Immediate expander-based breast reconstruction after mastectomy is a prevalent option for many women with breast cancer. When coupled with adjuvant radiation therapy,...
BACKGROUND
Immediate expander-based breast reconstruction after mastectomy is a prevalent option for many women with breast cancer. When coupled with adjuvant radiation therapy, however, radiation-induced skin and soft-tissue injury diminish the success of this reconstructive technique. The authors hypothesize that prophylactic administration of the cytoprotectant amifostine will reduce soft-tissue complications from irradiation, aiding expander-based reconstruction.
METHODS
Sprague-Dawley rats were divided into two groups: operative expander placement (expander group) and operative sham (sham group). Expander specimens received a sublatissimus tissue expander with a 15-cc fill volume; shams underwent identical procedures without expanders. Experimental groups were further divided into control specimens receiving no further intervention, radiation therapy-only specimens receiving human-equivalent irradiation, and amifostine plus radiation therapy specimens receiving both amifostine and human-equivalent irradiation. After a 45-day recovery period, animals were evaluated grossly and with ImageJ analysis for skin and soft-tissue complications.
RESULTS
None of the control, radiation therapy-alone, or amifostine plus radiation therapy sham specimens showed skin and soft-tissue complications. For expander animals, significantly fewer amifostine plus radiation therapy specimens [four of 13 (30 percent)] demonstrated skin and soft-tissue complications compared with radiation therapy-alone specimens [nine of 13 (69 percent); p = 0.041]. ImageJ evaluation of expander specimens demonstrated a significant increase in skin and soft-tissue necrosis for radiation therapy-alone specimens (12.94 percent) compared with animals receiving amifostine plus radiation therapy (6.96 percent) (p = 0.019).
CONCLUSIONS
Amifostine pretreatment significantly reduced skin and soft-tissue complications. These findings demonstrate that amifostine prophylaxis provides protection against radiation-induced skin and soft-tissue injury in a murine model of expander-based breast reconstruction.
Topics: Amifostine; Animals; Male; Mammaplasty; Models, Animal; Radiation Injuries; Radiation-Protective Agents; Rats; Rats, Sprague-Dawley; Tissue Expansion
PubMed: 25357049
DOI: 10.1097/PRS.0000000000000543 -
Scientific Reports Oct 2019Although multiple radioprotectors are currently being investigated preclinically for efficacy and safety, few studies have investigated concomitant metabolic changes....
Although multiple radioprotectors are currently being investigated preclinically for efficacy and safety, few studies have investigated concomitant metabolic changes. This study examines the effects of amifostine on the metabolic profiles in tissues of mice exposed to cobalt-60 total-body gamma-radiation. Global metabolomic and lipidomic changes were analyzed using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS) in bone marrow, jejunum, and lung samples of amifostine-treated and saline-treated control mice. Results demonstrate that radiation exposure leads to tissue specific metabolic responses that were corrected in part by treatment with amifostine in a drug-dose dependent manner. Bone marrow exhibited robust responses to radiation and was also highly responsive to protective effects of amifostine, while jejunum and lung showed only modest changes. Treatment with amifostine at 200 mg/kg prior to irradiation seemed to impart maximum survival benefit, while the lower dose of 50 mg/kg offered only limited survival benefit. These findings show that the administration of amifostine causes metabolic shifts that would provide an overall benefit to radiation injury and underscore the utility of metabolomics and lipidomics to determine the underlying physiological mechanisms involved in the radioprotective efficacy of amifostine. This approach may be helpful in identifying biomarkers for radioprotective efficacy of amifostine and other countermeasures under development.
Topics: Amifostine; Animals; Bone Marrow; Gamma Rays; Humans; Jejunum; Lung; Metabolomics; Mice; Radiation Exposure; Radiation-Protective Agents
PubMed: 31666611
DOI: 10.1038/s41598-019-52120-w -
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 -
Journal of Veterinary Science May 2023Titanium is the most widely used metal for bone integration, especially for cancer patients receiving ionizing radiation. This study aimed to investigate the amifostine...
BACKGROUND
Titanium is the most widely used metal for bone integration, especially for cancer patients receiving ionizing radiation. This study aimed to investigate the amifostine administration that would reduce the effects of radiation on bone healing and osseointegration in rat models.
OBJECTIVES
It is aimed that the application of amifostine in rats receiving radiotherapy treatment will reduce the negative effects of ionizing radiation on the bone.
METHODS
Thirty-five adult male Wistar rats were randomly divided into one healthy and four experimental groups. In three consecutive days, two experimental groups of rats (AMF-RT-IMP and RT-IMP) were exposed to radiation (15 Gy/3 fractions of 5 Gy each). Then the titanium implants were inserted into the left tibia. Before the radiotherapy process, a 200 mg/kg dose of amifostine (AMF) was administered to the rats in the AMF-IMP and AMF-RT-IMP groups. Twenty-eight days after the screw implant, all rats were sacrificed, and their blood samples and tibia bones were collected for analysis.
RESULTS
The results indicated an accelerated bone formation and a more rapid healing process in the screw implants in the AMF-IMP, AMF-RT-IMP, and AMF-RT groups than in the RT-IMP group. Also, bone-implant contact area measurement and inflammation decreased with amifostine treatment in the implants subjected to irradiation ( < 0.05).
CONCLUSIONS
The results obtained in the present study suggested that amifostine prevents the losses of bone minerals, bone integrity, and implant position from ionizing-radiation when given before exposure.
Topics: Rats; Male; Animals; Amifostine; Tibia; Titanium; Radiation-Protective Agents; Rats, Wistar
PubMed: 37271503
DOI: 10.4142/jvs.23023 -
Journal of Radiation Research Jan 2015This review gives a comparative evaluation of the radioprotective properties and the therapeutic index (TI) of radioprotectors from various pharmacological group in... (Comparative Study)
Comparative Study Review
This review gives a comparative evaluation of the radioprotective properties and the therapeutic index (TI) of radioprotectors from various pharmacological group in experiments on both small and large animals. It presents a hypothesis explaining the decrease in the TI of cystamine and 5-methoxytryptamine (mexamine), and the retention of that of α1-adrenomimetic indralin, and also compares the effects on large and small animals. The considerable differences in the therapeutic indices of catecholamines, serotonin and cystamine are a consequence of specific features of their mechanisms of radioprotective action. Radioprotectors acting via receptor mediation tend to provide a more expanded window of protection. The reduction in the TI of cystamine in larger animals, such as dogs, may be caused by the greater increase in toxicity of aminothiols in relation to the decrease in their optimal doses for radioprotective effect in going from mice to dogs, which is a consequence of the slower metabolic processes in larger animals. The somatogenic phase of intoxication by cystamine is significantly longer than the duration of its radioprotective effect, and increases with irradiation. The decrease in the radioprotective effect and the TI of mexamine in experiments with dogs may be caused by their lower sensitivity to the acute hypoxia induced by the mexamine. This is because of lower gradient in oxygen tension between tissue cells and blood capillaries under acute hypoxia that is determined by lower initial oxygen consumption in a large animal as compared with a small animal. Indralin likely provides optimal radioprotective effects and a higher TI for large animals via the increased specificity of its adrenergic effect on tissue respiration, which supports the development of acute hypoxia in the radiosensitive tissues of large animals. The stimulatory effect of indralin on early post-irradiation haematopoietic recovery cannot provide a high level of radioprotective action for large animals, but it may promote recovery.
Topics: 5-Methoxytryptamine; Adrenergic Agents; Amifostine; Animals; Cricetinae; Dogs; Dose-Response Relationship, Drug; Evidence-Based Medicine; Haplorhini; Mice; Radiation Injuries; Radiation Tolerance; Radiation-Protective Agents; Rats; Serotonin Agents; Species Specificity; Treatment Outcome
PubMed: 25312329
DOI: 10.1093/jrr/rru087 -
Journal of Reconstructive Microsurgery Oct 2022Radiation-associated soft tissue injury is a potentially devastating complication for head and neck cancer patients. The damage can range from minor sequelae such as... (Review)
Review
BACKGROUND
Radiation-associated soft tissue injury is a potentially devastating complication for head and neck cancer patients. The damage can range from minor sequelae such as xerostomia, which requires frequent daily maintenance, to destructive degenerative processes such as osteoradionecrosis, which can contribute to flap failure and delay or reverse oral rehabilitation. Despite the need for effective radioprotectants, the literature remains sparse, primarily focused on interventions beyond the surgeon's control, such as maintenance of good oral hygiene or modulation of radiation dose.
METHODS
This narrative review aggregates and explores noninvasive, systemic treatment modalities for prevention or amelioration of radiation-associated soft tissue injury.
RESULTS
We highlighted nine modalities with the most clinical potential, which include amifostine, melatonin, palifermin, hyperbaric oxygen therapy, photobiomodulation, pentoxifylline-tocopherol-clodronate, pravastatin, transforming growth factor-β modulators, and deferoxamine, and reviewed the benefits and limitations of each modality. Unfortunately, none of these modalities are supported by strong evidence for prophylaxis against radiation-associated soft tissue injury.
CONCLUSION
While we cannot endorse any of these nine modalities for immediate clinical use, they may prove fruitful areas for further investigation.
Topics: Amifostine; Deferoxamine; Fibroblast Growth Factor 7; Humans; Melatonin; Pravastatin; Soft Tissue Injuries; Transforming Growth Factors
PubMed: 35213927
DOI: 10.1055/s-0042-1742731 -
Oncotarget 2022DNA double strand breaks (DSBs) have been highly studied in the context of cancers, as DSBs can lead to apoptosis or tumorigenesis. Several pharmaceuticals are widely...
DNA double strand breaks (DSBs) have been highly studied in the context of cancers, as DSBs can lead to apoptosis or tumorigenesis. Several pharmaceuticals are widely used to target DSBs during cancer therapy. Amifostine (WR-2721) and etoposide are two commonly used drugs: amifostine reduces DSBs, whereas etoposide increases DSBs. Recently, a novel role for DSBs in immediate early gene expression, learning, and memory has been suggested. Neither amifostine nor etoposide have been assessed for their effects on learning and memory without confounding factors. Moreover, sex-dependent effects of these drugs have not been reported. We administered amifostine or etoposide to 3-4-month-old male and female C57Bl/6J mice before or after training in fear conditioning and assessed learning, memory, and immediate early genes. We observed sex-dependent baseline and drug-induced differences, with females expressing higher cFos and FosB levels than males. These were affected by both amifostine and etoposide. Post-training injections of amifostine affected long-term contextual fear memory; etoposide affected contextual and cued fear memory. These data support the hypothesis that DSBs contribute to learning and memory, and that these could play a part in cognitive side effects during common treatment regimens. The sex-dependent effects also highlight an important factor when considering treatment plans.
Topics: Amifostine; Animals; DNA; DNA Breaks, Double-Stranded; Etoposide; Female; Genes, Immediate-Early; Male; Memory, Long-Term; Mice; Neoplasms; Pharmaceutical Preparations
PubMed: 35106123
DOI: 10.18632/oncotarget.28180 -
International Journal of Reproductive... Apr 2019Cyclophosphamide (CP) is a well-known alkylating anticancer agent used in the treatment of various malignant and non-malignant tumors. CP may also cause a variety of...
BACKGROUND
Cyclophosphamide (CP) is a well-known alkylating anticancer agent used in the treatment of various malignant and non-malignant tumors. CP may also cause a variety of adverse effects, including reproductive toxicity. Amifostine is known as a cytoprotective drug having antioxidant properties.
OBJECTIVE
To evaluate the possible beneficial effects of amifostine on testicular toxicity induced by CP in rats.
MATERIALS AND METHODS
A total of 35 Sprague-Dawley rats were used in this experimental study. The CP group animals received a single dose of 200 mg/kg CP on Day 8 by intraperitoneal injection and were left untreated for the following seven days. The two remaining groups of animals were treated with 200 mg/kg/day amifostine (AMF 200) and 400 mg/kg/day amifostine (AMF 400) for seven days prior to and following a single intraperitoneal injection of CP. Morphometrical analysis and histological examination of testicular tissue were performed. Serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels were measured in serum using commercial ELISA kits. The epidydimal sperm count was determined.
RESULTS
The tubular epithelial height in the testis was significantly higher in the AMF400 group compared to other groups (p 0.001). Animals in the AMF400 group showed minimal debris in the tubules, no Sertoli cell damage, and the Johnsen scores were slightly higher in the AMF400 group. The epididymal sperm count was significantly lower in the CP-administered animals compared to the control animals and was significantly higher in the AMF200 and AMF400 groups compared to the CP group (p = 0.006, and p = 0.019 respectively).
CONCLUSION
Amifostine, at a dose of 400 mg/kg, may have a protective effect on testicular damage induced by CP in rats.
PubMed: 31435606
DOI: 10.18502/ijrm.v17i4.4549 -
Frontiers in Neurology 2017Peripheral neurotoxicity is a disturbing issue for cancer patients who are treated with chemotherapy. Several medications have been developed for preventing...
Peripheral neurotoxicity is a disturbing issue for cancer patients who are treated with chemotherapy. Several medications have been developed for preventing chemotherapy-induced chronic neurotoxicity (CICNT) however; their relative efficacies have not yet been studied. In this study, we conducted a network meta-analysis to give intervention recommendations. The literature was searched in a variety of databases and eligible studies were chosen based on predefined criteria. Data extraction and statistical analysis was performed, and the results are displayed using the odds ratio (OR) and corresponding 95% credible intervals (CrI) with respect to overall and severe neurotoxicity. The medications were ranked according to their surface under cumulative ranking curve values. The consistency of direct and indirect evidence was also evaluated. We found that patients with amifostine or vitamin E (VE) treatment exhibited a lower risk of overall neurotoxicity compared to those using the placebo (amifostine: OR = 0.10, 95% CrI: 0.02-0.46; VE: OR = 0.08, 95% CrI: 0.01-0.99). In regard to preventing severe neurotoxicity, glutathione and amifostine treatment appeared to be significantly more effective than the placebo (glutathione: OR = 0.19, 95% CrI: 0.04-0.64; amifostine: OR = 0.12, 95% CrI: 0.02-0.48). In summary, amifostine, VE, and glutathione treatment is considered to be effective in lowering the risk of CICNT. However, further studies which consider safety are required.
PubMed: 28642731
DOI: 10.3389/fneur.2017.00223 -
International Journal of Radiation... Dec 2018Oral mucositis is one of the most prevalent side effects in patients undergoing radiation therapy for head and neck cancers. Current therapeutic agents such as...
PURPOSE
Oral mucositis is one of the most prevalent side effects in patients undergoing radiation therapy for head and neck cancers. Current therapeutic agents such as palifermin recombinant human keratinocyte growth factor and amifostine do not efficiently or fully prevent mucositis. Dimethyl sulfoxide (DMSO), a free-radical scavenger, has shown therapeutic benefits in many preclinical and clinical studies. This study aimed to investigate the efficacy of DMSO in a clinically relevant mouse model of acute, radiation-induced oral mucositis.
METHODS AND MATERIALS
Oral mucositis was induced by a high single and fractioned irradiation of the head and neck area in C57BL/6J mice, and the effects of DMSO (by intraperitoneal injection) were assessed by macroscopic and histopathological examination. Epithelial stem and progenitor cells were analyzed by immunohistochemical staining of p63 and Ki-67, and DNA double-strand breaks (DSBs) were visualized by immunofluorescence detection of γ-H2AX. Tumor xenograft was obtained using CAL-27 cells.
RESULTS
Pretreatment with DMSO protected the oral mucosa from severe acute radiation injury, reduced the extent of radiation-induced weight loss, and had no significant effects on tumor weight in irradiated or nonirradiated xenograft mice. Furthermore, the efficacy of DMSO was superior to that of recombinant human keratinocyte growth factor and amifostine. DMSO treatment prevented the loss of proliferative lingual epithelial stem and progenitor cells upon irradiation. More interestingly, the average levels of γ-H2AX foci were significantly decreased in p63-positive epithelial stem cells at 6 hours, but not at 2 hours, after irradiation, indicating that DMSO facilitated DNA DSB repair rather than suppressing the indirect action of irradiation.
CONCLUSIONS
DMSO prevents the loss of proliferative lingual epithelial stem and progenitor cells upon irradiation by facilitating DNA DSB repair, thereby protecting against radiation-induced mucositis without tumor protection. Given its high efficacy and low toxicity, DMSO could be a potential treatment option to prevent radiation-induced oral mucositis.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; Dimethyl Sulfoxide; Dose-Response Relationship, Radiation; Epithelium; Head and Neck Neoplasms; Male; Mice; Mice, Inbred C57BL; Radiation Injuries, Experimental; Stem Cells; Stomatitis
PubMed: 30092334
DOI: 10.1016/j.ijrobp.2018.07.2010