-
Chinese Journal of Cancer Research =... Oct 2014Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However,... (Review)
Review
Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However, radiation-induced damage to normal tissues restricts the therapeutic doses of radiation that can be delivered to tumours and thereby limits the effectiveness of the treatment. The use of radioprotectors represents an obvious strategy to obtain better tumour control using a higher dose in radiotherapy. However, most of the synthetic radioprotective compounds studied have shown inadequate clinical efficacy owing to their inherent toxicity and high cost. Hence, the development of radioprotective agents with lower toxicity and an extended window of protection has attracted a great deal of attention, and the identification of alternative agents that are less toxic and highly effective is an absolute necessity. Recent studies have shown that alpha-2-macroglobulin (α2M) possesses radioprotective effects. α2M is a tetrameric, disulfide-rich plasma glycoprotein that functions as a non-selective inhibitor of different types of non-specific proteases and as a carrier of cytokines, growth factors, and hormones. α2M induces protein factors whose interplay underlies radioprotection, which supports the idea that α2M is the central effector of natural radioprotection in the rat. Pretreatment with α2M has also induced a significant reduction of irradiation-induced DNA damage and the complete restoration of liver and body weight. Mihailović et al. concluded that the radioprotection provided by α2M was in part mediated through cytoprotection of new blood cells produced in the bone marrow; these authors also indicated that an important aspect of the radioprotective effect of amifostine was the result of the induction of the endogenous cytoprotective capability of α2M. The radioprotective effects of α2M are possibly due to antioxidant, anti-fibrosis, and anti-inflammatory functions, as well as the maintenance of homeostasis, and enhancement of the DNA repair and cell recovery processes. This review is the first to summarise the observations and elucidate the possible mechanisms responsible for the beneficial effects of α2M. The lacunae in the existing knowledge and directions for future research are also addressed.
PubMed: 25400428
DOI: 10.3978/j.issn.1000-9604.2014.09.04 -
Biomedicines Oct 2020The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and... (Review)
Review
The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.
PubMed: 33142986
DOI: 10.3390/biomedicines8110461 -
Pharmaceutics Jun 2023The conventional dosage form of Ethyol (amifostine), a sterile lyophilized powder, involves reconstituting it with 9.7 mL of sterile 0.9% sodium chloride in accordance...
The conventional dosage form of Ethyol (amifostine), a sterile lyophilized powder, involves reconstituting it with 9.7 mL of sterile 0.9% sodium chloride in accordance with the United States Pharmacopeia specifications for intravenous infusion. The purpose of this study was to develop inhalable microparticles of amifostine (AMF) and compare the physicochemical properties and inhalation efficiency of AMF microparticles prepared by different methods (jet milling and wet ball milling) and different solvents (methanol, ethanol, chloroform, and toluene). Inhalable microparticles of AMF dry powder were prepared using a wet ball-milling process with polar and non-polar solvents to improve their efficacy when delivered through the pulmonary route. The wet ball-milling process was performed as follows: AMF (10 g), zirconia balls (50 g), and solvent (20 mL) were mixed and placed in a cylindrical stainless-steel jar. Wet ball milling was performed at 400 rpm for 15 min. The physicochemical properties and aerodynamic characteristics of the prepared samples were evaluated. The physicochemical properties of wet-ball-milled microparticles (WBM-M and WBM-E) using polar solvents were confirmed. Aerodynamic characterization was not used to measure the % fine particle fraction (% FPF) value in the raw AMF. The % FPF value of JM was 26.9 ± 5.8%. The % FPF values of the wet-ball-milled microparticles WBM-M and WBM-E prepared using polar solvents were 34.5 ± 0.2% and 27.9 ± 0.7%, respectively; while the % FPF values of the wet-ball-milled microparticles WBM-C and WBM-T prepared using non-polar solvents were 45.5 ± 0.6% and 44.7 ± 0.3%, respectively. Using a non-polar solvent in the wet ball-milling process resulted in a more homogeneous and stable crystal form of the fine AMF powder than using a polar solvent.
PubMed: 37376145
DOI: 10.3390/pharmaceutics15061696 -
European Journal of Medical Research Jan 2024Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions aimed at mitigating several different molecular aspects of the disease, only two drugs with limited clinical efficacy have so far been approved for IPF therapy.
OBJECTIVE
We investigated the therapeutic efficacy of amifostine, a detoxifying drug clinically used for radiation-caused cytotoxicity, in bleomycin-induced murine pulmonary fibrosis.
METHODS
C57BL6/J mice were intratracheally instilled with 3 U/kg of bleomycin. Three doses of amifostine (WR-2721, 200 mg/kg) were administered intraperitoneally on days 1, 3, and 5 after the bleomycin challenge. Bronchoalveolar lavage fluid (BALF) was collected on day 7 and day 21 for the assessment of lung inflammation, metabolites, and fibrotic injury. Human fibroblasts were treated in vitro with transforming growth factor beta 1 (TGF-β1), followed by amifostine (WR-1065, 1-4 µg/mL) treatment. The effects of TGF-β1 and amifostine on the mitochondrial production of reactive oxygen species (ROS) were assessed by live cell imaging of MitoSOX. Cellular metabolism was assessed by the extracellular acidification rate (ECAR), the oxygen consumption rate (OCR), and the concentrations of various energy-related metabolites as measured by mass spectrum (MS). Western blot analysis was performed to investigate the effect of amifostine on sirtuin 1 (SIRT1) and adenosine monophosphate activated kinase (AMPK).
RESULTS
Three doses of amifostine significantly attenuated lung inflammation and pulmonary fibrosis. Pretreatment and post-treatment of human fibroblast cells with amifostine blocked TGF-β1-induced mitochondrial ROS production and mitochondrial dysfunction in human fibroblast cells. Further, treatment of fibroblasts with TGF-β1 shifted energy metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) and towards glycolysis, as observed by an altered metabolite profile including a decreased ratio of NAD + /NADH and increased lactate concentration. Treatment with amifostine significantly restored energy metabolism and activated SIRT1, which in turn activated AMPK. The activation of AMPK was required to mediate the effects of amifostine on mitochondrial homeostasis and pulmonary fibrosis. This study provides evidence that repurposing of the clinically used drug amifostine may have therapeutic applications for IPF treatment.
CONCLUSION
Amifostine inhibits bleomycin-induced pulmonary fibrosis by restoring mitochondrial function and cellular metabolism.
Topics: Humans; Animals; Mice; Bleomycin; Transforming Growth Factor beta1; Amifostine; Sirtuin 1; AMP-Activated Protein Kinases; NAD; Reactive Oxygen Species; Lung; Idiopathic Pulmonary Fibrosis; Fibroblasts; Mitochondria; Pneumonia; Mice, Inbred C57BL
PubMed: 38245795
DOI: 10.1186/s40001-023-01623-4 -
The Lancet. Child & Adolescent Health Aug 2019The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss... (Review)
Review
The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss can impair speech-language acquisition development. Previous randomised trials assessed systemic drugs such as amifostine, sodium diethyldithiocarbamate or disulfiram, and sodium thiosulfate. Amifostine, sodium diethyldithiocarbamate, and disulfiram did not show hearing preservation. Paediatric trials assessing sodium thiosulfate showed efficacy in terms of hearing protection. The SIOPEL 6 trial consisted solely of patients with localised hepatoblastoma and no effects on survival were shown. In the ACCL0431 trial, which included heterogeneous patients, a post-hoc analysis showed significantly worse overall survival among patients who had disseminated disease receiving sodium thiosulfate than among controls, but not among those with localised disease. Intratympanically administered drugs have mainly been assessed in adults and include N-acetylcysteine and dexamethasone. Inconsistent effects of these drugs were identified but these studies were limited by design, small sample size, and statistical approach. Future studies of systemic drugs will need to consider the measurement of disease outcomes through study design and sample size, and ototoxicity endpoints should be harmonised to enhance comparability between trials.
Topics: Acetylcysteine; Adolescent; Amifostine; Anti-Inflammatory Agents; Antineoplastic Agents; Chelating Agents; Child; Cisplatin; Cytoprotection; Dexamethasone; Disulfiram; Ditiocarb; Humans; Neoplasms; Ototoxicity; Thiosulfates
PubMed: 31160205
DOI: 10.1016/S2352-4642(19)30115-4 -
Journal of Dental Research Aug 2018Varghese JJ, Schmale IL, Mickelsen D, Hansen ME, Newlands SD, Benoit DSW, Korshunov VA, Ovitt CE. 2018. Localized delivery of amifostine enhances salivary gland...
Varghese JJ, Schmale IL, Mickelsen D, Hansen ME, Newlands SD, Benoit DSW, Korshunov VA, Ovitt CE. 2018. Localized delivery of amifostine enhances salivary gland radioprotection. J Dent Res [epub ahead of print 10 April 2018] in press. (Original DOI: 10.1177/0022034518767408) In the original online article, the third author's name was misspelled as D. Mickelson. This has been corrected to D. Mickelsen online and in print.
PubMed: 29738287
DOI: 10.1177/0022034518774759 -
Molecules (Basel, Switzerland) Mar 2021Large doses of ionizing radiation can damage human tissues. Therefore, there is a need to investigate the radiation effects as well as identify effective and non-toxic...
Large doses of ionizing radiation can damage human tissues. Therefore, there is a need to investigate the radiation effects as well as identify effective and non-toxic radioprotectors. This study evaluated the radioprotective effects of Kelulut honey (KH) from stingless bee ( sp.) on zebrafish () embryos. Viable zebrafish embryos at 24 hpf were dechorionated and divided into four groups, namely untreated and non-irradiated, untreated and irradiated, KH pre-treatment and amifostine pre-treatment. The embryos were first treated with KH (8 mg/mL) or amifostine (4 mM) before irradiation at doses of 11 Gy to 20 Gy using gamma ray source, caesium-137 (Cs). Lethality and abnormality analysis were performed on all of the embryos in the study. Immunohistochemistry assay was also performed using selected proteins, namely γ-H2AX and caspase-3, to investigate DNA damages and incidences of apoptosis. KH was found to reduce coagulation effects at up to 20 Gy in the lethality analysis. The embryos developed combinations of abnormality, namely microphthalmia (M), body curvature and microphthalmia (BM), body curvature with microphthalmia and microcephaly (BMC), microphthalmia and pericardial oedema (MO), pericardial oedema (O), microphthalmia with microcephaly and pericardial oedema (MCO) and all of the abnormalities (AA). There were more abnormalities developed from 24 to 72 h (h) post-irradiation in all groups. At 96 h post-irradiation, KH was identified to reduce body curvature effect in the irradiated embryos (up to 16 Gy). γ-H2AX and caspase-3 intensities in the embryos pre-treated with KH were also found to be lower than the untreated group at gamma irradiation doses of 11 Gy to 20 Gy and 11 Gy to 19 Gy, respectively. KH was proven to increase the survival rate of zebrafish embryos and exhibited protection against organ-specific abnormality. KH was also found to possess cellular protective mechanism by reducing DNA damage and apoptosis proteins expression.
Topics: Amifostine; Animals; Apoptosis; Bees; DNA Damage; Gamma Rays; Histones; Honey; Radiation Injuries, Experimental; Radiation-Protective Agents; Zebrafish; Zebrafish Proteins
PubMed: 33809054
DOI: 10.3390/molecules26061557 -
Current Oncology (Toronto, Ont.) Apr 2023Despite high incidence rates and severe complications, the management of xerostomia lacks clinical guidelines. The aim of this overview was to summarize the clinical... (Review)
Review
Despite high incidence rates and severe complications, the management of xerostomia lacks clinical guidelines. The aim of this overview was to summarize the clinical experience derived from the last 10 years of treatments and prevention using systemic compounds. Results showed that the cytoprotective drug amifostine, and its antioxidant agents, are the most discussed as preventive agents of xerostomia in head and neck cancer (HNC) patients. In the presence of the disease, the pharmacological treatments have been mainly directed to stimulate secretion of the damaged salivary glands, or to counteract a decreased capacity of the antioxidant system, in view of an increasing of reactive oxygen species (ROS). However, the data demonstrated low ability of the drugs, together with a great number of side effects, which strongly limit their use. Concerning traditional medicine (TM), valid clinical trials are so limited that neither the efficacy nor the absence of interferences to concomitant chemical therapies can be validated. Consequently, the management of xerostomia and its devastating complications remain a very significant void in daily clinical practice.
Topics: Humans; Radiation-Protective Agents; Antioxidants; Xerostomia; Amifostine; Medicine, Traditional
PubMed: 37232794
DOI: 10.3390/curroncol30050336 -
Frontiers in Oncology 2021Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to...
Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including . Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the promoter a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.
PubMed: 34900719
DOI: 10.3389/fonc.2021.769385 -
Frontiers in Immunology 2023Squamous cell carcinoma of the anus (SCCA) is a rare gastrointestinal cancer. Factors associated with progression of HPV infection to anal dysplasia and cancer are...
BACKGROUND
Squamous cell carcinoma of the anus (SCCA) is a rare gastrointestinal cancer. Factors associated with progression of HPV infection to anal dysplasia and cancer are unclear and screening guidelines and approaches for anal dysplasia are less clear than for cervical dysplasia. One potential contributing factor is the anorectal microbiome. In this study, we aimed to identify differences in anal microbiome composition in the settings of HPV infection, anal dysplasia, and anal cancer in this rare disease.
METHODS
Patients were enrolled in two prospective studies. Patients with anal dysplasia were part of a cross-sectional cohort that enrolled women with high-grade lower genital tract dysplasia. Anorectal tumor swabs were prospectively collected from patients with biopsy-confirmed locally advanced SCCA prior to receiving standard-of-care chemoradiotherapy (CRT). Patients with high-grade lower genital tract dysplasia without anal dysplasia were considered high-risk (HR Normal). 16S V4 rRNA Microbiome sequencing was performed for anal swabs. Alpha and Beta Diversity and composition were compared for HR Normal, anal dysplasia, and anal cancer.
RESULTS
60 patients with high-grade lower genital tract dysplasia were initially enrolled. Seven patients had concurrent anal dysplasia and 44 patients were considered HR Normal. Anorectal swabs from 21 patients with localized SCCA were included, sequenced, and analyzed in the study. Analysis of weighted and unweighted UniFrac distances demonstrated significant differences in microbial community composition between anal cancer and HR normal (p0.018). LEfSe identified that all three groups exhibited differential enrichment of specific taxa. (p=0.028), (p=0.0295) (p=0.034) (p=0.029) were enriched in anal cancer specimens when compared to HR normal.
CONCLUSION
Although alpha diversity was similar between HR Normal, dysplasia and cancer patients, composition differed significantly between the three groups. Increased anorectal , , and abundance were associated with anal cancer. These organisms have been reported in various gastrointestinal cancers with roles in facilitating the proinflammatory microenvironment and neoplasia progression. Future work should investigate a potential role of microbiome analysis in screening for anal dysplasia and investigation into potential mechanisms of how these microbial imbalances influence the immune system and anal carcinogenesis.
Topics: Humans; Female; Papillomavirus Infections; Prospective Studies; Cross-Sectional Studies; Anus Neoplasms; Carcinoma, Squamous Cell; Microbiota; Tumor Microenvironment
PubMed: 37063829
DOI: 10.3389/fimmu.2023.1051431