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.
Amifostine ; Computer Simulation ; Cytostatic Agents ; Drug Discovery ; Drug Therapy ; Humans ; Quantitative Structure-Activity Relationship ; Radiation Tolerance ; Radiotherapy ; United States Food and Drug Administration

OBJECTIVES: Radioiodine (RI) therapy is known to subject cellular components of salivary glands (SG) to oxidative stress leading to SG dysfunction. However, the protective effects of antioxidants on RI-induced SG damage have not been well investigated. The authors investigated the morphometric and functional effects of epigallocatechin-3-gallate (EGCG) administered prior to RI therapy and compared this with the effects of amifostine (a well-known antioxidant) in a murine model of RI sialadenitis. METHODS: Four-week-old female C57BL/6 mice (n=48) were divided into four groups; a normal control group, a RI-treated group (0.01 mCi/g mouse, orally), an EGCG and RI-treated group, and an amifostine and RI-treated group. Animals in these groups were divided into 3 subgroups and euthanized at 15, 30, and 90 days post-RI treatment. Salivary flow rates and lag times were measured, and morphologic and histologic examinations and TUNEL (terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling) assays were performed. Changes in salivary (99m)Tc pertechnetate uptake and excretion were followed by single-photon emission computed tomography. RESULTS: Salivary flow rates and lag times to salivation in the EGCG or amifostine groups were better than in the RI-treated group. Histologic examinations of SGs in the EGCG or amifostine group showed more mucin-rich parenchyma and less periductal fibrosis than in the RI-treated group. Fewer apoptotic cells were observed in acini, ducts, and among endothelial cells in the EGCG or amifostine group than in the RI group. In addition, patterns of (99m)Tc pertechnetate excretion were quite different in the EGCG or amifostine group than in the RI group. CONCLUSION: EGCG supplementation before RI therapy could protect from RI-induced SG damage in a manner comparable to amifostine, and thus, offers a possible means of preventing SG damage by RI.
Amifostine ; Animals ; Antioxidants ; DNA Nucleotidylexotransferase ; Endothelial Cells ; Female ; Fibrosis ; Humans ; In Situ Nick-End Labeling ; Mice ; Models, Animal ; Oxidative Stress ; Salivary Glands* ; Salivation ; Sialadenitis ; Sodium Pertechnetate Tc 99m ; Thyroid Neoplasms ; Tomography, Emission-Computed ; Tomography, Emission-Computed, Single-Photon

Radioactive iodine (131I) targets the thyroid gland and has been proven to play an effective role in the treatment of differentiated thyroid cancers. However, this radioisotope is simultaneously absorbed on the salivary glands where it is concentrated and secreted into the saliva. Dose related damage to the salivary parenchyma results from the 131I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of 131I and/or months later and progress in intensity with time. Prevention of the 131I-induced sialadenitis includes the use of sialagogic agents to enhance the transit time of the 131I through the salivary glands. However, many studies are not available to delineate the efficacy of this approach. Recently, amifostine has been advocated to prevent the effects of irradiation. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialagogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration.
Amifostine ; Anti-Bacterial Agents ; Iodine ; Massage ; Mouthwashes ; Oral Hygiene ; Radioactivity ; Saliva ; Salivary Glands ; Sialadenitis* ; Thyroid Gland

This study was purposed to investigate the protective effects of lipoprotein HS-6101(6101) on rhesus monkey total body irradiated with 7.0 Gy ⁶⁰Coγ-ray. A total of 30 health adult rhesus monkeys were randomly divided into symptomatic therapy (ST), WR2721 and HS-6101 30, 90 and 270 mg/kg groups (n = 6), the rhesus monkeys of each groups were injected with physiological saline 0.3 ml/kg, WR-2721 30 mg/kg, or HS-6101 30, 90 and 270 µg/kg, respectively. All agents were once intramuscularly injected at 1 hr prior irradiation. General observation, peripheral blood cell counts, colony forming unite assay of bone marrow hemopoietic progenitor cells, and histopathological examination were performed. The results showed that animals in symptomatic therapy group begin to die on the 13(th) day and 4 animals died within 24 days, the average survival time was 18.2 ± 4.3 days; 2 animals in WR-2717 groups died on day 15.8 and day 18.5 post irradiation respectively. 1 animal in HS-6101 270 mg/kg group died on day 35.8, all other animals survived. Nadirs of peripheral blood white blood cells, neutrophils and platelets of animals in HS-6101 treatment groups were significantly higher than those in other 2 groups including ST and WR-2721 groups, and the hemopoietic recovery were also significantly speeding up(P < 0.05 and 0.01). In vitro results showed that HS-6101 obviously promoted 7.0 Gy ⁶⁰Coγ irradiated monkey's bone marrow mononuclear cells to form various hematopoietic progenitor cell colonies (P < 0.05 and 0.01) . Compared with symptomatic therapy and WR-2717 groups, bone marrow histopathological changes in HS-6101 treatment groups showed more active hemopoietic cell proliferation and higher density structure. It is concluded that HS-6101 90 µg/kg treatment can promote the bone marrow recovery of 7.0 Gy ⁶⁰Coγ irradiated monkey, alleviate their animal symptom, simplify the treatment measures and improve the animal survival rate. The HS-6101 shows remarkable radioprotective effects as compared with the currently internationally acknowledged radioprotectant of WR-2721.
Amifostine ; Animals ; Blood Cell Count ; Blood Platelets ; Bone Marrow ; Bone Marrow Cells ; Hematopoietic Stem Cells ; Hematopoietic System ; drug effects ; radiation effects ; Lipoproteins ; pharmacology ; Macaca mulatta ; Radiation Injuries ; drug therapy ; Survival Rate

The aim of this study was to investigate the effect of WR2721(amifostine) against bone marrow hematopoietic damage of mice exposed to 6.5 Gy of (60)Co-γ ray. A total of 60 C57/BL6J mice was divided into 3 groups:normal group (mice were injected with physiological salt solution), irradiation group (mice were injected with physiologic salt solution before irradiation) and WR2721 group (mice were injected with WR2721 before irradiation). The WBC, neutrophil (Neut), Plt and RBC levels in peripheral blood of 3 group mice were counted within 60 days after irradiation; the bone marrow nuclear cells (BMNC) were counted at 2 and 24 hours after irradiation; the hematopoietic stem/progenitor cell (LK/LSK) level and colony formation capability were detected by flow cytometry at 2 and 24 hours after irradiation. The results indicated that the counts of WBC and neut at 4 and 18 days, Plt at 7-18 days and RBC at 10-30 day after irradiation in WR2721 group were higher than those in irradiation group (P < 0.05); the BMNC, LSK and LK levels obviously increased at 24 hours after irradiation (P < 0.05), the CFU-GEMM, CFU-GM, CFU-MK BFU-E and CFU-E all significantly increased at 2 and 24 hours after irradiation (P < 0.01), as compared with irradiation group. It is concluded that WR2721 can effectively alleviate early hematopoietic damage and promote the fast recovery of peripheral blood cells in mice exposed to γ-ray, suggesting that the WR2721 has significant radioprotective effect on hematopoietic system.
Amifostine ; pharmacology ; Animals ; Blood Cell Count ; Bone Marrow Cells ; cytology ; drug effects ; radiation effects ; Gamma Rays ; Hematopoietic Stem Cells ; cytology ; drug effects ; radiation effects ; Male ; Mice ; Mice, Inbred C57BL ; Radiation-Protective Agents ; pharmacology ; Whole-Body Irradiation

Objective of this study was to perform bioinformatics analysis of the characteristics of gene expression profiling regulated by amifostine and predict its novel potential biological function to provide a direction for further exploring pharmacological actions of amifostine and study methods. Amifostine was used as a key word to search internet-based free gene expression database including GEO, affymetrix gene chip database, GenBank, SAGE, GeneCard, InterPro, ProtoNet, UniProt and BLOCKS and the sifted amifostine-regulated gene expression profiling data was subjected to validity testing, gene expression difference analysis and functional clustering and gene annotation. The results showed that only one data of gene expression profiling regulated by amifostine was sifted from GEO database (accession: GSE3212). Through validity testing and gene expression difference analysis, significant difference (p < 0.01) was only found in 2.14% of the whole genome (460/192000). Gene annotation analysis showed that 139 out of 460 genes were known genes, in which 77 genes were up-regulated and 62 genes were down-regulated. 13 out of 139 genes were newly expressed following amifostine treatment of K562 cells, however expression of 5 genes was completely inhibited. Functional clustering displayed that 139 genes were divided into 11 categories and their biological function was involved in hematopoietic and immunologic regulation, apoptosis and cell cycle. It is concluded that bioinformatics method can be applied to analysis of gene expression profiling regulated by amifostine. Amifostine has a regulatory effect on human gene expression profiling and this action is mainly presented in biological processes including hematopoiesis, immunologic regulation, apoptosis and cell cycle and so on. The effect of amifostine on human gene expression need to be further testified in experimental condition.
Amifostine ; pharmacology ; Computational Biology ; Gene Expression ; drug effects ; Gene Expression Profiling ; methods ; Humans ; Microarray Analysis ; Molecular Sequence Annotation

This in vitro study evaluated the detrimental effect of acute gamma (gamma)-irradiation on rat immature hippocampal neurons. Rat immature hippocampal neurons (0.5 day in vitro) were irradiated with 0~4 Gy gamma-rays. Cytotoxicity was analyzed using a lactate dehydrogenase release assay at 24 h after gamma-irradiation. Radiation-induced cytotoxicity in immature hippocampal neurons increased in a dose-dependent manner. Pre-treatments of pro-apoptotic caspase inhibitors and anti-oxidative substances significantly blocked gamma-irradiation-induced cytotoxicity in immature hippocampal neurons. The results suggest that the caspase-dependent cytotoxicity of gamma-rays in immature hippocampal cultured neurons may be caused by oxidative stress.
Amifostine/pharmacology ; Animals ; Antioxidants/pharmacology ; Caspase 3/metabolism/radiation effects ; Catechin/analogs & derivatives/pharmacology ; Cell Survival/radiation effects ; Cells, Cultured/cytology/enzymology/*radiation effects ; Dose-Response Relationship, Radiation ; Female ; *Gamma Rays ; Hippocampus/cytology/enzymology/*radiation effects ; L-Lactate Dehydrogenase/radiation effects ; Neurons/cytology/enzymology/*radiation effects ; Poly(ADP-ribose) Polymerases/drug effects ; Pregnancy ; Rats ; Rats, Sprague-Dawley

This study was designed to assess the feasibility of calcium phosphate cement/amifostine complex as a new material for filling the bone defect caused by tumor resection. Mixed-molding method was used, the mass ratios of 0%, 0.1%, 0.5%, 1%, 2% of amifostine/calcium phosphate cement complex being adopted. The curing time, mechanical strength, porosity, scanning electron micrograph, osteosarcoma cells' vitality and vascular endothelial cells' vitality relevant to the complex in vitro were observed. Calcium phosphate cement being loaded with 0.1% and 0.5% amifostine did not affect the curing time, strength, pore size and porosity of calcium phosphate bone cement. In addition proliferation and differentiation of osteosarcoma cells and vascular endothelial cells were not affected. These data suggest that phosphate cement containing 0.1% and 0.5% amifostine be of significance in the treatment regimen as bone defect filling materials..
Amifostine ; pharmacology ; Bone Cements ; pharmacology ; Calcium Phosphates ; pharmacology ; Cell Line, Tumor ; Cell Survival ; drug effects ; Cells, Cultured ; Chemical Phenomena ; Endothelial Cells ; cytology ; drug effects ; Humans ; Osteosarcoma ; pathology

OBJECTIVETo investigate the feasibility of using calcium phosphate cement/amifostine complex as an new filling material for repairing bone defect caused by tumor resection.

METHODSCalcium phosphate cement (CPC)/cisplatin/amifostine complex was prepared at the mass ratio of 1000:2:5. The setting time, mechanical strength, and porosity of the complex were determined, and scanning electron microscopy and assessment of sustained drug release and inhibitory effect against osteosarcoma cells were carried out. The degradation of the material and new bone ingrowth were also observed in a rabbit model of femoral bone defect.

RESULTSThe setting time, strength, and porosity, appearances under scanning electron microscope, and sustained drug release properties of CPC/cisplatin/amifostine complex were identical to those of CPC, and the integration of amifostine in the complex did not affect the cytotoxicity of cisplatin against the osteosarcoma cells. Pathological evidences of the degradation of the material and new bone ingrowth into the material were observed with the passage of time following its implantation into the bone defect in rabbits.

CONCLUSIONThe CPC/cisplatin/amifostine complex can be used as a filling material for repairing bone defect caused by tumor resection and eliminating the residual tumor cells in rabbits.

Amifostine ; administration & dosage ; Animals ; Bone Cements ; therapeutic use ; Calcium Phosphates ; administration & dosage ; Cisplatin ; administration & dosage ; Delayed-Action Preparations ; chemical synthesis ; Female ; Femoral Neoplasms ; surgery ; therapy ; Implants, Experimental ; Male ; Osteosarcoma ; surgery ; therapy ; Porosity ; Rabbits

Amifostine ; therapeutic use ; Animals ; Head and Neck Neoplasms ; radiotherapy ; Humans ; Oral Health ; Radiation Injuries ; etiology ; prevention & control ; therapy ; Radiation-Protective Agents ; therapeutic use ; Radiotherapy ; adverse effects ; Radiotherapy, Conformal ; Salivary Glands ; radiation effects ; Salivation ; radiation effects ; Submandibular Gland ; surgery ; transplantation ; Xerostomia ; etiology ; prevention & control ; therapy