BACKGROUND: In a previous study, we have shown that quinolones, antibiotics inhibiting topoisomerases, improve survival of tumor cells under hypoxic conditions. In this study, we tested whether antitumor agents such as doxorubicin that inhibit topoisomerases can also improve survival of tumor cells under hypoxic conditions. METHODS: Human hepatocellular carcinoma cells (HepG2) were grown in 4 mL of the culture medium at 2.5x10(5) cells/60 mm culture dish under normoxic conditions for 2 days before being transferred to fresh culture medium with different concentrations of doxorubicin or other antitumor agents under normoxic or hypoxic (1% oxygen concentration in air) conditions. Cell viability and the concentration of glucose and lactic acid in the medium were measured during cell culture. At the same time, the cells in the 60 mm dishes were lysed, and chromosomal DNA was isolated and loaded onto a 1.5% agarose gel for the DNA fragmentation assay. RESULTS: Doxorubicin inhibited cell growth under normoxic condition in a concentration-dependent manner for the 0~100 microgram/mL concentration range. However, doxorubicin improved cell viability under hypoxic conditions for a 0.1~10 microgram/mL concentration range by inhibiting apoptosis. Similar phenomena were observed for other antitumor agents that inhibit topoisomerases. CONCLUSIONS: Solid tumors usually have hypoxic regions in the tumor, under which conditions antitumor agents that inhibit topoisomerases may function to delay tumor cell death. This can reduce the efficacy of the antitumor agents.
Anoxia ; Anti-Bacterial Agents ; Antineoplastic Agents* ; Apoptosis ; Carcinoma, Hepatocellular* ; Cell Culture Techniques ; Cell Death ; Cell Survival ; DNA ; DNA Fragmentation ; Doxorubicin ; Glucose ; Humans* ; Lactic Acid ; Oxygen ; Quinolones ; Sepharose

BACKGROUND: Hemodilution reduces the concentration of clotting factors in blood and it may induce some degree of coagulation impairment. The goal of this study is to investigate the changes of coagulation status during progressive hemodilution with several solutions. METHODS: Sixty healthy patients were randomly allocated to six groups according to experimental solution, and each group contained 10 patients. Whole blood was diluted by 0%, 10%, 25%, 50% with 0.9% normal saline, 4% modified fluid gelatin, 10% pentastarch, 10% dextran 40 and two brands of 6% hydroxyethyl starchs (Salinehes(R) , HAES-steril(R) ). At each dilution, thromboelastographic parameters {(r, k, alpha angle, maximum amplitude (MA)} were measured using thromboelastography (TEG) and were compared with those of an undiluted specimen obtained concurrently from the same patients. RESULTS: Hemodilutions of 25% and 50% with 0.9% normal saline decreased r and k times, and increased alpha angle but there was no difference in MA. Hemodilutions of 10% and 25% with modified gelatin solution did not change the parameters. However, 50% hemodilution of the gelatin solution decreased the k time and increased alpha angle. Hemodilutions of more than 10% with 10% pentastarch increased the k time, decreased alpha angle and MA. Hemodilutions of more than 10% with 10% dextran 40 increased r and k times, and decreased alpha angles and MA according to the quantities of this dilutional solution. Hemodilutions of more than 25% with 10% dextran 40 increased k times above 400%. Hemodilutions of more than 10% of 6% HES (Salinehes(R) , M.W: 70,000 dalton) decreased MA. Hemodilutions of more than 10% of 6% HES (HAES-steril(R) , M.W: 200,000 dalton) decreased the alpha angle. CONCLUSIONS: 25% and 50% hemodilutions of 0.9% normal saline induce a hypercoagulable state, but hemodilutions of more than 10% with each colloid solution decreased coagulability of whole blood according to the degree of dilution, except in the case of modified fluid gelatin solution. Hemodilutions of more than 25% with 10% dextran 40 induce a severe coagulation impairment.
Colloids ; Dextrans ; Gelatin ; Hemodilution* ; Humans ; Hydroxyethyl Starch Derivatives ; Starch ; Thrombelastography*

OBJECTIVE: Using functional magnetic resonance imaging, cerebral language areas were determined during a series of language tasks in normal strong right-handed subjects. METHODS: Twelve normal right-handed volunteers were examined on a 1.5T MR unit. Language task paradigms included two phonological tasks involving meaningless letters and sentences, and four semantic tasks using different types of words. Each language task was examined using a separate scan consisted of three blocks separated by rest periods. BOLD (blood oxygenation level dependent) signals during language tasks were compared using 24 sec alternating rest periods during which subjects concentrated on a plus symbol. After preprocessing and statistically analyzing individual data, group analysis (p<0.001, k=50) was performed using SPM99 software. RESULTS: Meaningless letter reading was more efficient than sentence reading, in terms of delineating brain regions related to phonological processing, we found significant regions in the left inferior frontal gyrus (IFG), left thalamus, bilateral cingulate gyri, right anterior superior temporal gyrus (STG), right IFG, and left inferior parietal lobule (IPL). During semantic tasks, left IFG, left posterior middle temporal gyrus, left IPL, bilateral medial frontal gyrus, right posterior STG, right parahippocampal, and fusiform gyri were found to be activated. CONCLUSION: During the two phonological tasks, normal strongly right-handed people more actively used the left IFG, right anterior temporal lobe, and right IFG than during semantic processing, whereas during the four semantic tasks, these subjects more actively used the bilateral posterior temporal and right medial temporal lobes.
Brain ; Magnetic Resonance Imaging* ; Oxygen ; Rabeprazole ; Semantics* ; Temporal Lobe ; Thalamus ; Volunteers

PURPOSE: In a previous study, we have shown that anticancer agents inhibiting topoisomerases improve survival of tumor cells under hypoxic condition. In the present study, we evaluated whether and how cell survival effect of the anticancer agents under hypoxic conditions could be eliminated by the addition of nitroimidazoles, a class of bioreductive agents. METHODS: Human hepatocellular carcinoma cells (HepG2) were incubated with different combinations of pimonidazole (1~1,000 microg/ml) and doxorubicin (0.1 or 1 microg/ml) concentrations under different O2 concentrations [1, 3, 5, 10 and 21 O2]. Then cell numbers, glucose concentrations and lactic acid concentrations in the medium were measured, and DNA fragmentation assay was performed. Finally, different combinations of nitroimidazoles, such as pimonidazole, misonidazole, etanidazole, tinidazole, metronidazole, ornidazole or dimetridazole, and anticancer agents, such as doxorubicin, campothecin, epirubicin, dactinomycin, etoposide or mitomycin C was added to the cell culture medium under hypoxic conditions (1% O2). RESULTS: Pimonidazole at a concentration of 100 microg/ml eliminated cell survival effect of doxorubicin at the concentrations of 0.1 and 1 microg/ml under hypoxic condition (1% O2) by promoting apoptosis. Almost all the cells died even after 24 hours of incubation for all the oxygen concentrations at a combination of 100 microg/ml pimonidazole and 1 microg/ml doxorubicin. Finally, pimonidazole at a concentration of 100 microg/ml, and misonidazole or etanidazole at a concentration of 1,000 microg/ml eliminated cell survival effect of all the anticancer agents tested under hypoxic condition. CONCLUSION: Combination therapy of doxorubicin (adriamycin) with pimonidazole can maximize dororubicin efficacy by eliminating cell survival effect of doxorubicin under hypoxic conditions in treating solid tumors, such as breast cancer.
Anoxia ; Antineoplastic Agents ; Apoptosis ; Breast Neoplasms ; Carcinoma, Hepatocellular ; Cell Count ; Cell Culture Techniques ; Cell Survival ; Dactinomycin ; Dimetridazole ; DNA Fragmentation ; Doxorubicin ; Epirubicin ; Etanidazole ; Etoposide ; Glucose ; Humans ; Lactic Acid ; Metronidazole ; Misonidazole ; Mitomycin ; Nitroimidazoles ; Ornidazole ; Oxygen ; Tinidazole

BACKGROUND/AIMS: While gastric variceal bleeding (GVB) is not as prevalent as esophageal variceal bleeding, it is reportedly more serious, with high failure rates of the initial hemostasis (>30%), and has a worse prognosis than esophageal variceal bleeding. However, there is limited information regarding hemostasis and the prognosis for GVB. The aim of this study was to determine retrospectively the clinical outcomes of GVB in a multicenter study in Korea. METHODS: The data of 1,308 episodes of GVB (males:females=1062:246, age=55.0+/-11.0 years, mean+/-SD) were collected from 24 referral hospital centers in South Korea between March 2003 and December 2008. The rates of initial hemostasis failure, rebleeding, and mortality within 5 days and 6 weeks of the index bleed were evaluated. RESULTS: The initial hemostasis failed in 6.1% of the patients, and this was associated with the Child-Pugh score [odds ratio (OR)=1.619; P<0.001] and the treatment modality: endoscopic variceal ligation, endoscopic variceal obturation, and balloon-occluded retrograde transvenous obliteration vs. endoscopic sclerotherapy, transjugular intrahepatic portosystemic shunt, and balloon tamponade (OR=0.221, P<0.001). Rebleeding developed in 11.5% of the patients, and was significantly associated with Child-Pugh score (OR=1.159, P<0.001) and treatment modality (OR=0.619, P=0.026). The GVB-associated mortality was 10.3%; mortality in these cases was associated with Child-Pugh score (OR=1.795, P<0.001) and the treatment modality for the initial hemostasis (OR=0.467, P=0.001). CONCLUSIONS: The clinical outcome for GVB was better for the present cohort than in previous reports. Initial hemostasis failure, rebleeding, and mortality due to GVB were universally associated with the severity of liver cirrhosis.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; Endoscopy ; Esophageal and Gastric Varices/*diagnosis/mortality/therapy ; Female ; *Gastrointestinal Hemorrhage ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Prognosis ; Republic of Korea ; Retrospective Studies ; Sclerotherapy ; Severity of Illness Index ; Treatment Outcome ; Young Adult