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Scientific Reports Feb 2019Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with...
Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.
Topics: Administration, Oral; Amifostine; Animals; Female; Intestine, Small; Male; Mercaptoethylamines; Mice; Mice, Inbred C57BL; Pancreatic Neoplasms; Radiation Dosage; Radiation Protection; Radiation-Protective Agents
PubMed: 30760738
DOI: 10.1038/s41598-018-37147-9 -
Stem Cells International 2019This study is aimed at investigating the effect of amifostine (AMI) on rat bone marrow stromal stem cells (BMSCs) exposed to 2 Gy radiation. The BMSCs were divided...
This study is aimed at investigating the effect of amifostine (AMI) on rat bone marrow stromal stem cells (BMSCs) exposed to 2 Gy radiation. The BMSCs were divided into four groups, namely, group A that received 0 Gy radiation, group B that received 0 Gy radiation and AMI, group C that received 2 Gy radiation, and group D that received 2 Gy radiation and AMI. The proliferation, apoptosis, and distribution of BMSCs in the cell cycle, along with their osteogenesis ability, adipogenesis ability, and ROS production, were subsequently examined. The levels of ALP, PPAR, P53, and TNF were determined by Western blotting. The results demonstrated that the proliferation of BMSCs and the levels of ALP in group C were much lower than those in group A. The production of ROS and levels of PPAR, P53, and TNF in the group that received 2 Gy radiation were much higher than those in group A. Furthermore, the production of ROS and the levels of PPAR, P53, and TNF were much lower in group D than in group C. Additionally, the levels of ALP and extent of cell proliferation were much higher in group D than in group C. The results demonstrated the potential of AMI in reducing the side effects of radiation in BMSCs and in treatment of bone diseases caused by radiation.
PubMed: 30728842
DOI: 10.1155/2019/8749090 -
Radiation Oncology Journal Dec 2018Cancer is a complex multifaceted illness that affects different patients in discrete ways. For a number of cancers the use of chemotherapy has become standard practice....
Cancer is a complex multifaceted illness that affects different patients in discrete ways. For a number of cancers the use of chemotherapy has become standard practice. Chemotherapy is a use of cytostatic drugs to cure cancer. Cytostatic agents not only affect cancer cells but also affect the growth of normal cells; leading to side effects. Because of this, radiotherapy gained importance in treating cancer. Slaughtering of cancerous cells by radiotherapy depends on the radiosensitivity of the tumor cells. Efforts to improve the therapeutic ratio have resulted in the development of compounds that increase the radiosensitivity of tumor cells or protect the normal cells from the effects of radiation. Amifostine is the only chemical radioprotector approved by the US Food and Drug Administration (FDA), but due to its side effect and toxicity, use of this compound was also failed. Hence the use of herbal radioprotectors bearing pharmacological properties is concentrated due to their low toxicity and efficacy. Notably, in silico methods can expedite drug discovery process, to lessen the compounds with unfavorable pharmacological properties at an early stage of drug development. Hence a detailed perspective of these properties, in accordance with their prediction and measurement, are pivotal for a successful identification of radioprotectors by drug discovery process.
PubMed: 30630265
DOI: 10.3857/roj.2018.00381 -
World Journal of Clinical Oncology Jan 2019Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for... (Review)
Review
Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for reduction of xerostomia burden vary widely, with options including: sialagogue medications, saliva substitutes, acupuncture, vitamins, hyperbaric oxygen, submandibular gland transfer, and acupuncture or associated treatments. In this review, we sought to evaluate long-term outcomes of patients treated with various interventions for radiation-induced xerostomia. A literature search was performed using the terms "xerostomia" and "radiation" or "radiotherapy"; all prospective clinical trials were evaluated, and only studies that reported 1 year follow up were included. The search results yielded 2193 studies, 1977 of which were in English. Of those, 304 were clinical trials or clinical studies. After abstract review, 23 trials were included in the review evaluating the following treatment modalities: pilocarpine (three); cevimeline (one); amifostine (eleven); submandibular gland transfer (five); acupuncture like transcutaneous electrical nerve stimulation (ALTENS) (one); hyperbaric oxygen (one); and acupuncture (one). Pilocarpine, cevimeline, and amifostine have been shown in some studies to improve xerostomia outcomes, at the cost of toxicity. ALTENS has similar efficacy with fewer side effects. Submandibular gland transfer is effective but requires an elective surgery, and thus may not always be appropriate or practical. The use of intensity-modulated radiation therapy, in addition to dose de-escalation in select patients, may result in fewer patients with late xerostomia, reducing the need for additional interventions.
PubMed: 30627521
DOI: 10.5306/wjco.v10.i1.1 -
Oxidative Medicine and Cellular... 2018This study aims at investigating the radioprotective effect of ethanol extract from Ji-Xue-Teng (JXT, ) on radiation-induced hematopoietic alteration and oxidative...
This study aims at investigating the radioprotective effect of ethanol extract from Ji-Xue-Teng (JXT, ) on radiation-induced hematopoietic alteration and oxidative stress in the liver. Mice were exposed to a single acute -radiation for the whole body at the dose of 6.0 Gy, then subjected to administration of amifostine (45 mg/kg) or JXT (40 g crude drug/kg) once a day for 28 consecutive days, respectively. Bone marrow cells and hemogram including white cells, red cells, platelet counts, and hemoglobin level were examined. The protein expression levels of pJAK2/JAK2, pSTAT5a/STAT5a, pSTAT5b/STAT5b, and Bcl-2 in bone marrow tissue; levels of reactive oxygen species (ROS); and the activity of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in serum and liver tissue were determined. At the end of the experiment, the effect of JXT on cell viability and G-CSF and G-CSFR levels in NFS-60 cells were tested by CCK-8 assay, ELISA, and flow cytometry. The results showed that the mice exposed to -radiation alone exhibited a typical hematopoietic syndrome. In contrast, at the end of the 28-day experiment, irradiated mice subjected to oral administration of JXT showed an obvious improvement on blood profile with reduced leucopenia, thrombocytopenia (platelet counts), RBC, and hemoglobin levels, as well as bone marrow cells. The expression of pJAK2/JAK2, pSTAT5a/STAT5a, and Bcl-2 in bone marrow tissue was increased after JXT treatment. The elevation of ROS was due to radiation-induced toxicity, but JXT significantly reduced the ROS level in serum and liver tissue, elevated endogenous SOD and GSH-PX levels, and reduced the MDA level in the liver. JXT could also increase cell viability and G-CSFR level in NFS-60 cells, which was similar to exogenous G-CSF. Our findings suggested that oral administration of JXT effectively facilitated the recovery of hematopoietic bone marrow damage and oxidative stress of the mice induced by -radiation.
Topics: Antioxidants; Cells, Cultured; Gamma Rays; Humans; Ipomoea batatas; Liver; Oxidative Stress; Plant Extracts; Plant Leaves; Protective Agents; Reactive Oxygen Species
PubMed: 30510630
DOI: 10.1155/2018/9017835 -
Lung Cancer (Auckland, N.Z.) 2018Concurrent chemoradiotherapy is considered a standard option for patients with stage 3 small cell lung carcinoma. A 25% risk of acute esophagitis is experienced by...
OBJECTIVES
Concurrent chemoradiotherapy is considered a standard option for patients with stage 3 small cell lung carcinoma. A 25% risk of acute esophagitis is experienced by patients as a result of the volume of esophagus encompassed within a conformal radiotherapy technique. We reviewed our institutional experience administering the radioprotectant amifostine prior to daily radiotherapy to determine its effects on the onset of esophagitis.
MATERIALS AND METHODS
From 2005 to 2016, 49 patients diagnosed with stage 3 small cell lung carcinoma received concurrent chemoradiotherapy. Chemotherapy (CT) consisted of cisplatin and etoposide with radiotherapy (RT) encompassing CT-identified gross tumor volume. In 32 patients (group 1), amifostine was delivered (500 mg subcutaneously divided in two injections) prior to the second daily RT fraction. The remaining 17 patients (group 2) did not receive amifostine due to choice or drug intolerance.
RESULTS
Metrics of esophagitis included weight loss and opiate requirement during treatment. About 31% of group 1 required opiates at a median RT dose of 3300 cGy, and 41% of group 2 required opiates at a median dose of 2250 cGy. The dose of radiotherapy delivered to 50% of the esophageal volume for group 1 was significantly greater than that in group 2 (3000 cGy vs 576 cGy).
CONCLUSION
In this modern retrospective series of thoracic chemoradiotherapy in the treatment of stage 3 small cell lung cancer, amifostine that was delivered subcutaneously postponed the onset of esophagitis.
PubMed: 30237747
DOI: 10.2147/LCTT.S155315 -
International Journal of Molecular... Aug 2018Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate...
Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate amifostine effects on doxorubicin-induced toxic changes in rats. Amifostine (75 mg/kg ip) was given 30 min before each dose of doxorubicin (cumulatively 20 mg/kg ip, for 28 days). The animals' whole-body, liver, and kidney weight, serum biochemical examination, as well as microscopic examination of bone marrow, peripheral blood, liver, and kidney, were done on day 56 of the study. Hepatic and renal alterations were carefully quantified by semiquantitative grading scales-hepatic and renal damage score, respectively. In amifostine-pretreated rats, the number of peripheral blood leukocytes was significantly higher in comparison to doxorubicin-only treated group, preferentially protecting neutrophils. In the same group of rats, hepatic and renal alterations associated with polymorphonuclear cell infiltrates were significantly less severe than those observed in animals receiving only doxorubicin. Our results showed that amifostine successfully protected rats against multiple-dose doxorubicin-induced toxicity by complex, and still not fully elucidated mechanisms of action.
Topics: Amifostine; Animals; Chemical and Drug Induced Liver Injury; Doxorubicin; Kidney Diseases; Male; Organ Specificity; Rats; Rats, Wistar
PubMed: 30103540
DOI: 10.3390/ijms19082370 -
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 -
Chinese Journal of Cancer Research =... Jun 2018The radioprotective effects of amifostine remain uncertain in patients with nasopharyngeal carcinoma (NPC), and adverse effects and cost limit generalization of its...
OBJECTIVE
The radioprotective effects of amifostine remain uncertain in patients with nasopharyngeal carcinoma (NPC), and adverse effects and cost limit generalization of its classical everyday regimen. This phase II multicenter randomized controlled trial aimed to explore whether amifostine could ameliorate the toxicities of NPC patients in the era of intensity-modulated radiotherapy (IMRT), and to compare different regimens of amifostine on effectiveness and safety.
METHODS
Patients with stage I-IVB NPC were involved prospectively from January 1st, 2013. All patients received radical treatment based on IMRT. After a randomization stratified by their stage, these patients were allocated into 3 groups: the group treated without amifostine, the group treated with the everyday regimen of amifostine, and the group treated with the every-other-day regimen. The 3 groups of patients were compared on radiotherapy-related acute toxicities, treatment effects of NPC, and amifostine-related complications. This trial was registered on the clinicaltrials.gov (ID: NCT01762514).
RESULTS
Until August 31st, 2017, totally 187 patients completed experimental intervention. Only amifostine of everyday regimen appeared to reduce the patient proportion of mucositis (79.1% . 96.8%, P=0.002). Hypocalcemia was less common in patients treated without amifostine than in those treated with amifostine (22.6% . 53.4% . 41.8%, P=0.002). Neither complete remission rates nor the survivals were affected by amifostine.
CONCLUSIONS
Amifostine of everyday regimen could reduce mucositis in NPC patients who received IMRT, though it also had the possibility to cause more hypocalcemia.
PubMed: 30046225
DOI: 10.21147/j.issn.1000-9604.2018.03.03 -
Journal of Veterinary Research Dec 2017Radioactive iodine (RAI) is commonly used for the treatment of hyperthyroidism caused by Graves' disease or thyroid nodules. However, information available on the impact...
INTRODUCTION
Radioactive 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 METHODS
In 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.
RESULTS
The 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.
CONCLUSION
All histopathological parameters and some spermatological parameters showed that RAI therapy caused statistically significant damage of testicular tissue and this damage was reduced by amifostine.
PubMed: 29978117
DOI: 10.1515/jvetres-2017-0064