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| 1 | Preclinical evaluation of azathioprine plus buthionine sulfoximine in the treatment of human hepatocarcinoma and colon carcinoma显示文摘AIM: To evaluate the efficacy and the safety of azathioprine (AZA) and buthionine sulfoximine (BSO) bylocalized application into HepG2 tumor in vivo.METHODS: Different hepatoma and colon carcinoma cell lines (HepG2, HuH7, Chang liver, LoVo, RKO, SW-48, SW-480) were grown in minimal essencial medium supplemented with 10% fetal bovine serum and 1% antibiotic/antimycotic solution and maintained in a humidified 37 ℃ incubator with 5% CO2. These cells were pretreated with BSO for 24 h and then with AZA for different times. We examined the effects of this combination on some proteins and on cellular death. We also studied the eff icacy and the safety of AZA (6 mg/kg per day) and BSO (90 mg/kg per day) in HepG2 tumor growth in vivo using athymic mice. We measured safety by serological markers such as aminotransferases and creatine kinase.RESULTS: The in vitro studies revealed a new mechanism of action for the AZA plus BSO combination in the cancer cells compared with other thiopurines (6-mercaptopurine, 6-methylmercaptopurine, 6-thioguanine and 6-methylthioguanine) in combination with BSO. The cytotoxic effect of AZA plus BSO in HepG2 cells resulted from necroptosis induction in a mitochondrial-dependent manner. From kinetic studies we suggest that glutathione (GSH) depletion stimulates c-Jun amino-terminal kinase and Bax translocation in HepG2 cells with subsequent deregulation of mitochondria (cytochrome c release, loss of membrane potential), and proteolysis activation leading to loss of membrane integrity, release of lactate dehydrogenase and DNA degradation. Some of this biochemical and cellular changes could be reversed by N-acetylcysteine (a GSH replenisher). In vivo studies showed that HepG2 tumor growth was inhibited when AZA was combined with BSO.CONCLUSION: Our studies suggest that a combination of AZA plus BSO could be useful for localizedtreatment of hepatocellular carcinoma as in the currently used transarterial chemoembolization method. | Borja Hernández-Breijo Jorge Monserrat Sara Ramírez-Rubio Eva P Cuevas Diana Vara Inés Díaz-Laviada M Dolores Fernández-Moreno Irene D Román Javier P Gisbert Luis G Guijarro | 2011 | World Journal of Gastroenterology2011，17，34： | 2 |
| 2 | a quantitative analysis显示文摘 | LASLETT G M GREEN P F DUDDY I R et' al Thermal annealing of fission tracks in apatite 2 | 1987 | Chemical Geology1987，65，1： | 1 |
| 3 | Evaluation of oxy-gen transfer efficiency and alpha factor on a variety of diffusedaeration system显示文摘 | Groves K P Daigger G T Simpk in T J et at | 1992 | Water Environment Research1992，64，5： | 1 |
| 4 | 显示文摘 | Rahman M McVetty P B E,Li G Y,Development of SRAP1SNP and multiplexed SCAR molecular markers for the major seed coat color gene in Brassica rapa L | 2007 | Theoretical and Applied Genetics2007，115，8： | 1 |
| 5 | Effects of the Inclu2sion of Yeast Culture (Saccharomyces Plus Growth Modium) in the Diet of Dairy Cows on Milk Yield and Forage Degradation and Fermentation Patterns in the Rumen of Steers显示文摘 | Williams P E V Tait C A Ines G M | 1991 | J Anim Sci1991，69，： | 1 |
| 6 | Significant tests and analysis of covariance structures 显示文摘 | Bentler P M Bonett D goodness of fit in the G | 1980 | Psychological Bulletin1980，，88： | 1 |
| 7 | Preparation of lithium-boron al oys:electrochemical studies as anodes in molt en salt media and comparisonwith pure lithium-involving syst ems显示文摘 | Sanchez P Bel in C Crepy G | | 0，，： | 1 |
| 8 | internal structure studied by fluorescence nonradiative energy transfer 显示文摘 | Marion P Beinert G Juhue D et aL Core -shell latex particles containing a fluorinated polymer in the shell 2 | 1997 | Macromolecules1997，30，1： | 1 |
| 9 | Scr Metall 显示文摘 | Huis A J in't Veld Boom G Bronsveld P M | 1985 | 19:11231985，19，： | 1 |
| 10 | constitutive nuclear fact or s显示文摘 | Kaufmann J A Bickford P C Taglialatela G dependent change in the aged hippocampu 1 928 | 2002 | Neuro report2002，13，15： | 1 |
| 11 | Temporal variations of the structure of a laser beam in the surface layer of the atmosphere显示文摘 | Vakhmyanin K P II'V V in | 1999 | Opt Technol1999，66，11： | 1 |
| 12 | Matrix interference free determination of perchlorate in urine by ion association-ion chromatography-mass spectrometry 显示文摘 | MARTINELANGO P G(3L(IN GOM DASGUPTA P | 2006 | Analytica Chimica Acta2006，567，1： | 1 |
| 13 | Heavy mineral distribution sediments from the eastern continental India and their implications on palaeoenvironment显示文摘 | Mislankar P G in the surficial margin of Gujar A R | 1996 | Indian Journal of Earth Sciences1996，23，34： | 1 |
| 14 | Definition and diagnostic criteria of ref-ractory ascites and hepatorenal syndrome in cirrhosis 显示文摘 | Arroyo V G ines P Gerbes AL | 1996 | Hepatology1996，23，： | 1 |
| 15 | Investigation on the fuel spray and emission reduction characteristics for dimethyl ether (DME) fueled multi-cylinder diesel engine with common-rail injection system显示文摘 | IN M Y SU H P HYUN G R | 2011 | Fuel Processing Technology2011，92，7： | 1 |
| 16 | A nteriorapproach w ith expandable cage im plantation in m anagement of unstable thoracolum bar fractu res: results of aseries of 93 p atien ts显示文摘 | T hom as G K aissar F P atric k R Benjam in B e t al | | N eurochirurgie0，62，2： | 1 |
| 17 | Cyathenoisn A, a spiropyranosyl derivative of protocatechuic acid from Cythea phalerata 显示文摘 | Moacir G P Ines M C B Adailton J B | 2007 | Phytochemistry2007，68，： | 1 |
| 18 | Numerical simulation of the in- ception of channel meandering 显示文摘 | Depth-averaged 2-D calcula- transport in curved channels of Sediment Research 2004 Duan J G Julien P Y | 2005 | Earth Surface Process and Landforms2005，30，9： | 1 |
| 19 | Probiotics for treatment of a- cute diarrhoea in children: randomised clinical trial of five different preparations 显示文摘 | RB Canani P Cirillo G Ten'in | 2007 | BMJ2007，335，7615： | 1 |
| 20 | A re port of two cases显示文摘 | OLUTOYE O O JOHNSON M P COLEMAN B G Abnormal umbilical cord Doppler sonograms may predict im pending demise in fetuses with sacrococcygeal teratoma | 2003 | Fetal Diagn Ther2003，19，1： | 1 |
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