[Show abstract][Hide abstract] ABSTRACT: Reirradiation is a challenging field in the treatment of recurrent brain metastases. Because of the elevated risk of radiation toxicity due to previous irradiation, only a limited dose is prescribed. To enhance radiosensitivity, in the present analysis six patients received hypofractionated stereotactic radiotherapy (hSRT) with daily oral administration of the hypoxic sensitizer AK-2123 (sanazole) for progressive brain metastases after previous radiotherapy. The patients received daily oral administration of 1.0 g/day sanazole up to 2 h before radiotherapy. Three partial and three stable responses were observed, with no sanazole-related toxicity, except for a case of mild nausea. Brain failure with subsequent death occurred in one patient. The other patients maintained good performance status until disease progression in other lesions. hSRT with a hypoxic radiation sensitizer appears to have the potential to enhance the efficacy of radiotherapy.
Anticancer research 04/2013; 33(4):1773-6. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Glioblastoma has a very poor prognosis even after incorporation into therapy of the newly-developed drug, temozolomide. Case Report: We present a case of 62-year-old woman with glioblastoma multiforme treated with tomotherapy intensity-modulated radiation therapy using simultaneous integrated boost technique (SIB-IMRT) along with a daily oral dose of a hypoxic radiation sensitizer, sanazole (AK-2123). SIB-IMRT was administered at a dose of 60 Gy in 20 fractions for high-risk planning target volume (PTV) and at 40 Gy for low-risk PTV. The patient received an oral administration of sanazole (1.0 g/day) for 10 days, 2 h before radiotherapy. She achieved a complete response without any adverse events, and remained disease-free for 3.5 years. Our study demonstrates that the higher single-dose radiotherapy combined with a hypoxic radiation sensitizer has the potential to enhance the efficacy of radiotherapy.
Anticancer research 04/2013; 33(4):1685-8. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the feasibility of daily oral administration of the hypoxic tumor radiation sensitizer, sanazole (AK-2123).
We analyzed the toxicity associated with 44 treatments of 42 patients, who received daily oral administration of 1 g/day sanazole (level A, 1-9g, 12 treatments; Level B, 10 g, 33 treatments) 2 h before radiotherapy. Eligibility criteria were as follows: Patients who were unable to receive standard treatment because of older age and/or fragile status and/or refractory disease. Five patients with advanced tumors treated with pre- or postoperative adjuvant radiotherapy were also included.
Toxicity was assessed during 44 treatment sessions. Eight patients (18%) showed sanazole-related paresthesia in the extremities, similar to the rate (15%) reported in a preceding multi-institutional international phase III study, which used intravenous administration. No sanazole-related toxicity rated grade 3 or higher was observed. Forty out of the 44 treatment sessions (91%) were completed.
This study validates the feasibility of daily oral administration of sanazole. Further studies to establish suitable applications are warranted.
Anticancer research 02/2013; 33(2):643-6. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim: To investigate the potential of the anti-oxidant ascorbic acid glucoside (AA-2G) to modulate neurotoxicity induced by high doses of nitrotriazole radiosensitizer. Materials and Methods: Male and female C56Bl/6xCBA hybrid mice aged 8-14 weeks (weight 18-24 g) were used. Nitrotriazole drug radiosensitizer sanazole at a high dose of 2, 1 g/kg was per os administered to induce neurotoxicity at mice. Ascorbic acid glucoside was given 30 min before the sanazole administration. Serum ascorbic acid, brain glutathione level, as well as behavioral performance using open field apparatus were measured. Results: Administration of high (non-therapeutic) doses of the nitrotriazole drug sanazole results in neurotoxicity in mice as evidenced from behavioral performance, emotional activity and depletion of the cellular antioxidant, glutathione, in the brain. The serum levels of ascorbic acid was also found reduced in high dose sanazole treated animals. Per os administration of ascorbic acid glucoside significantly reduced the neurotoxicity. This effect was associated with the prevention of glutathione depletion in mouse brain and restoring the ascorbic acid level in serum. Conclusion: Administration of ascorbic acid glucoside, but not ascorbic acid, before sanazole administration protected from sanazole-induced neurotoxicity by preventing the decrease in the brain reduced glutathione level and providing high level of ascorbic acid in plasma.
Journal of cancer research and therapeutics 01/2013; 9(3):364-369. · 0.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Silver nanoparticles were prepared from silver nitrate using a vitamin C derivative, 6-palmitoyl ascorbic acid-2-glucoside (PAsAG), via a sonochemical experiment. The resultant golden yellow solution that contained silver nanoparticle-PAsAG complex (SN-PAsAG) of about 5 nm particle sizes was explored for its potential to offer protection to DNA from γ-radiation-induced damages. The presence of SN-PAsAG during irradiation inhibited the disappearance of covalently closed circular (ccc) form of plasmid pBR322 with a dose modifying factor of 1.78. SN-PAsAG protected cellular DNA from radiation-induced damage as evident from comet assay study on mouse spleen cells, irradiated ex vivo. When orally administered with SN-PAsAG at 1 hour prior to whole-body radiation exposure, cellular DNA was found protected from radiation-induced strand breaks in various tissues (spleen cells, bone marrow cells, and blood leucocytes) of animals. Also, SN-PAsAG could enhance the rate of repair of cellular DNA in blood leucocytes and bone marrow cells when administered immediately after radiation exposure. The studies, under in vitro, ex vivo, and in vivo radiation exposure conditions, showed effective radiation protection.
Cancer Biotherapy & Radiopharmaceuticals 04/2011; 26(2):249-57. · 1.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extraskeletal Ewing's sarcoma is a rare soft tissue tumor that is morphologically indistinguishable from Ewing's sarcoma of bone. We report a case of extraskeletal Ewing's sarcoma with several systemic problems. A 69-year-old man presented with a 5-month history of a rapidly enlarging mass in the right thigh. Because preoperative radiotherapy with sanazole (AK-2123) contributed the tumor mass reduction down to 40% in size, the tumor was successfully resected with clear surgical margins and repaired with a musculocutaneous flap. The high efficacy of pre-operative low-dose radiotherapy with sanazole was histologically confirmed that the resected tumor specimen involved no viable tumor cells and showed 100% necrosis. Based on clinical outcomes in this case, the combined modality of pre-operative low-dose radiotherapy with hypoxic cell radiosensitizer and adequate surgical resection might provide for the useful clinical application of extraskeletal Ewing's sarcoma treatment.
[Show abstract][Hide abstract] ABSTRACT: Whole-body exposure of mice to gamma radiation leads to depletion of tissue antioxidant defence and damages the haematopoietic and gastrointestinal systems in mice. Administration of ascorbic acid-2-glucoside (AsAG) at a dose of 100 mg/kg body weight could prevent the radiation-induced reduction of total White Blood Cell (WBC) count and decrease in bone marrow viability following whole-body radiation. An enhanced spleen colony formation was also observed in whole-body irradiated mice administered with AsAG. Administration of AsAG also protected the epithelial cells of the gastrointestinal tract from the radiation-induced structural alterations. The generation of Reactive Oxygen Species (ROS) in tissues due to radiation exposure depletes the antioxidant defence systems and increase the peroxidative damage to membrane lipids, and the administration of AsAG prior to irradiation protected the tissue antioxidant system and membrane lipids from the radiation-induced damage.
Int. J. of Low Radiation. 01/2010; 7(5):380 - 392.
[Show abstract][Hide abstract] ABSTRACT: The effects of TMG [2-(alpha-d-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol], a water-soluble vitamin E derivative, administered after irradiation on the mortality of X-irradiated mice and on the development of tumors in the mammary and pituitary glands in rats were investigated. When TMG (650 mg/kg) was administered intraperitoneally (i.p.) to C3H mice immediately after whole-body exposure to 7 Gy radiation, the 30-day survival was significantly higher than that of the control mice. The i.p. administration of TMG at 4 h after irradiation significantly improved survival compared to that of the controls, but administration 8 h after irradiation did not have a significant effect. Subcutaneous administration of TMG immediately after irradiation also decreased mortality significantly. When dams of lactating Wister rats were exposed to 1.5 Gy of X rays at day 21 after parturition and were then treated with diethylstilbestrol as a tumor promoter, the incidence of mammary tumors and pituitary tumors was increased compared to that in the nonirradiated control group. The administration of TMG (600 mg/kg, i.p.) after irradiation significantly reduced the incidence of mammary tumors and pituitary tumors. The number of rats that were free of both mammary and pituitary gland tumors was enhanced fourfold by TMG. These results suggest that TMG is effective in preventing radiation-induced bone marrow death in mice and in reducing mammary and pituitary tumors in rats even when it is administered after irradiation.
Radiation Research 10/2009; 172(4):519-24. · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A palmitoyl derivative of ascorbic acid 2-glucoside, 6-palmitoyl ascorbic acid-2-glucoside (PAsAG), which possess good antioxidant properties, is examined for radioprotection in vitro, ex vivo and in vivo models. PAsAG protected plasmid DNA from gamma-radiation induced damages under in vitro conditions. Presence of 1.6 mM PAsAG inhibited the disappearance of ccc (covalently closed circular) form of plasmid pBR322 with a dose modifying factor of 1.5. Comet assay studies on mouse spleen cells exposed to 6 Gy gamma-radiation (ex vivo) in presence and absence of PAsAG revealed that cellular DNA was effectively protected by this compound from radiation induced damages. Oral administration of 80 mg/kg body weight of PAsAG to mice 1 hour prior to 6 Gy whole body gamma-radiation exposure, efficiently protected cellular DNA in tissues such as spleen, bone marrow and blood, from radiation induced damages as indicated by alkaline comet assay. Oxidative stress in tissues such as liver and brain of mice, following whole body exposure to various doses of gamma-radiation (2-8 Gy), monitored as levels of GSH and peroxidation of lipids, were found considerably reduced when PAsAG was orally administered (80 mg/kg body weight) to the mice one hour prior to the radiation exposure. PAsAG administration improved the per cent survival of mice following exposure to 10 Gy whole body gamma-radiation. Thus PAsAG could act as a radioprotector under in vitro, ex vivo and in vivo conditions of ionizing-radiation exposure.
Journal of Radiation Research 05/2009; 50(3):203-12. · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sanazole has been tested clinically as a hypoxic cell radiosensitizer. In this study, we determined whether sanazole enhances the radiation-induced apoptosis of human lymphoma U937 cells. Our results revealed that, compared with 10 mM sanazole or radiation alone, the combination of both resulted in a significant enhancement of apoptosis after 6 h, which was evaluated on the basis of DNA fragmentation, morphological changes, and phosphatidylserine externalization. Sanazole alone enhanced intracellular superoxide and hydrogen peroxide formation, which further increased when the cells were irradiated. Significant enhancement of Fas externalization, loss of mitochondrial membrane potential (MMP), and activation of caspase-3 and caspase-8 were observed after the combined treatment. Moreover, this combination could also enhance Bid activation, reduction of Hsp70 expression level and release of cytochrome c from the mitochondria to the cytosol. An immediate increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) was observed after the combined treatment. These results suggest that the intracellular superoxide and peroxide generated by sanazole might be involved in the enhancement of radiation-induced apoptosis, and that these effects are associated with modulation of the Fas-mitochondria-caspase-dependent pathway, an increase in [Ca(2+)](i), and a decrease in the Hsp70 expression levels.
[Show abstract][Hide abstract] ABSTRACT: Cisplatin is one of the most widely used cytotoxic therapeutic agents for the treatment of cancer. This drug, at effective higher doses, causes many physiological adverse effects such as nephrotoxicity and genotoxicity. The toxicity of the drug has been attributed to the induction of oxidative free radicals.
Following intraperitoneal administration of cisplatin and ascorbic acid monoglucoside (AsAG) or alpha-tocopherol monoglucoside (TMG), investigations were conducted on levels of serum urea and creatinine, peroxidation of lipids in renal tissues, renal antioxidants and histopathology of renal tissue.
Administration of cisplatin to mice induced a marked renal failure, characterized by significant increase in serum urea and creatinine levels in addition to severe alterations in renal tissue architecture. Cisplatin also induced oxidative stress as indicated by increased lipid peroxidation and decreased levels of reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase in renal tissues. Administration of AsAG or TMG markedly reduced the cisplatin-induced higher plasma creatinine and urea levels and counteracted the deleterious effects of cisplatin on oxidative stress markers and protected the tissues from the cisplatin-induced lipid peroxidation.
These results indicated that AsAG or TMG has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of AsAG or TMG in human application for protecting against drug-induced nephrotoxicity.
Experimental and Toxicologic Pathology 09/2008; 60(6):521-7. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Effects of ascorbic acid (AA), ascorbic acid glycoside (AAG) and alpha-tocopherol monoglycoside (TMG) on radiation - and H(2)O(2)-induced decomposition of thymine in aqueous solutions were investigated. Of the three compounds studied, AAG was found to possess the most marked protector properties. An explanation of this phenomenon has been given in terms of differences in molecular structures of AA and AAG, as well as properties of radical adducts formed during their interaction with OH radicals.
Journal of Radiation Research 08/2008; 49(4):431-5. · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In vivo radioprotection of C3H mice by i.p. administration of Zn-, Mn-, Cu-, or Se-containing heat-treated Saccharomyces serevisiae yeast sample was examined. The 30-day survival of the group treated 30 min before 7.5 Gy whole-body X-irradiation with mineral-containing yeast powders suspended in 0.5% methylcellulose was significantly higher than that of control group. When mineral-yeast was administered immediately after irradiation, the survival rate was even higher and Zn- or Cu-yeast showed the highest rate (more than 90%). Although treatment with simple yeast showed a high survival rate (73%), it was significantly lower than that obtained by the Zn-yeast treatment. The effects of Zn-yeast were studied further. When the interval between irradiation and administration was varied, the protective activity of Zn-yeast decreased gradually by increasing the interval but was still significantly high for the administration at 10 h post-irradiation. The dose reduction factor of Zn-yeast (100 mg/kg, i.p. administration immediately after irradiation) was about 1.2. When the suspension of Zn-yeast was fractionated by centrifugation, the insoluble fraction showed a potent effect, while the soluble fraction had only a moderate effect. In conclusion, mineral-yeast, especially Zn-yeast, provides remarkable post-irradiation protection against lethal whole body X-irradiation. The activity is mainly attributable to the insoluble fraction, whereas some soluble components might contribute to the additional protective activity.
Journal of Radiation Research 08/2008; 49(4):425-30. · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ascorbic acid monoglucoside (AsAG), a glucoside derivative of ascorbic acid, has been examined for its antioxidant and radioprotective abilities. AsAG neutralized 1, 1 diphenyl -2-picryl-hydrazyl (DPPH), a stable free radical in a concentration dependent manner thus indicating its antioxidant ability. AsAG protected mice liver tissues in vitro from peroxidative damage in lipids (measured as TBARS) resulting from 25Gy gamma irradiation. It also protected plasmid pBR322 DNA from gamma-radiation induced strand breaks as evidenced from studies on agarose gel electrophoresis of the plasmid DNA after radiation exposure. Oral administration of AsAG to mice prior to whole body gamma radiation exposure (4Gy) resulted in a reduction of radiation induced lipid peroxides in the liver tissue indicating in vivo radiation protection of membranes. Pulse radiolysis studies indicated that AsAG offered radioprotection by scavenging free radicals. The rate constants for the reactions OH and N(3) radicals with AsAG were determined to be 6.4 x 10(9) dm(3) mol(-1) s(-1) and 2.3 x 10(9) dm(3) mol(-1) s(-1), respectively at pH 7. It was observed that AsAG radicals undergo conjugation as the pH of the solution is raised to 11 in the case of a one-electron oxidation reaction. As the OH(*) radical adds to the ring, the conjugation effect starts appearing at pH 10.
Journal of Radiation Research 10/2007; 48(5):369-76. · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Damage to cellular DNA and its repair in the peripheral blood leucocytes of mice exposed to 4 Gy whole-body gamma-radiation was studied by alkaline single cell gel electrophoresis or comet assay. The comet parameters of DNA, such as comet tail length, % of DNA in tail, tail moment and olive tail moment, were found increased in the leucocytes from irradiated animals due to radiation-induced DNA strand breaks. The strand breaks in cellular DNA were repaired in a time dependent manner as evidenced from the decrease in the comet parameters. Thus, 15 minutes after irradiation exposure, 15% of DNA strand breaks were repaired and at 90 minutes post-irradiation, 43% were repaired. When tocopherol monoglucoside was administered to mice following radiation, it was found that at 15 and 90 minutes post-irradiation, 64% and 67% DNA, respectively, were repaired. This would suggest that administration of tocopherol monoglucoside enhanced the repair of cellular DNA damage in whole-body irradiated mice. However, in vitro studies, either with humans or mice, peripheral blood leucocytes showed that the presence of tocopherol monoglucoside (0.5 mM) in post-irradiation incubation medium did not enhance the repair of DNA strand breaks.
International Journal of Low Radiation 01/2007; 4(1):43 - 52.
[Show abstract][Hide abstract] ABSTRACT: The formation of products resulting from the O-glycoside bond cleavage following radiolysis of aqueous solutions of methyl-alpha-D-glucopyranoside (I), 3-O-methyl-alpha-D-glucopyranose (II), maltose, lactose, gentiobiose and cellobiose were studied. Radiation-induced destruction yields were also determined for dextran, laminarin and trimethylcelulose upon irradiation of their aqueous solutions. Oxygen, quinones and compounds capable of forming quinoid structures were found to inhibit radiation-induced homolytic destruction processes taking place in glycosides, di- and polysaccharides. The data obtained in this study enabled the authors to demonstrate an important role played by the fragmentation reaction of C-2 radicals which were generated from the starting substances in the formation of final radiolysis products.
Journal of Radiation Research 10/2005; 46(3):319-24. · 1.69 Impact Factor