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Guoxin Zhang,
Seon-Ah Ha,
Hyun K Kim,
Jinah Yoo,
Sanghee Kim,
Youn S Lee,
Soo Y Hur,
Yong W Kim,
Tae E Kim,
Yong G Park, [......],
Yang Yang,
Zekuan Xu,
Eun Y Song,
Zuhu Huang,
Peng Jirun,
Jin Zhongtian,
Qiao Shishi,
Cui Zhuqingqing,
Gong Lei, Jin W Kim
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ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors in the world. The only serological marker widely used for the diagnosis of HCC is alpha-fetoprotein (AFP). Despite that AFP is widely used for the diagnosis of HCC, it has a limit as a serological marker due to its low sensitivity and specificity. The human cervical cancer proto-oncogene 1 (HCCR-1) was previously reported as a new biomarker for HCC. To further evaluate the HCCR-1 as a biomarker for HCC, we conducted the prospective cohort study. We evaluated the significance of simultaneous measurement of 2 tumor markers in the diagnosis of HCC in China, Japan and Korea. Two markers for HCC, AFP and HCCR-1, were measured in the sera obtained from 1,338 patients at the time of initial diagnosis of HCC. Of the 1338 HCC patients, 616 (46%) and 686 (51.3%) were sero-positive for AFP and HCCR-1, respectively. The positive rate for HCC was increased up to 74.1% in combined use of AFP and HCCR-1. Many cases (54%) for AFP-negative HCC were positive for HCCR-1 and vice versa. More importantly, the diagnostic rate for small HCC (< 2 cm) was significantly improved in the combined analysis of AFP and HCCR-1 to 56.9% although it was only 40.1% and 23.4% in the single analysis of HCCR-1 and AFP, respectively. Our result suggests that the HCCR-1 could be an useful biomarker for HCC while the diagnostic rate could be significantly improved in the combined use of HCCR-1 and AFP.
Disease markers 01/2012; 32(4):265-71. · 1.64 Impact Factor
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Seon-Ah Ha,
Hyun K Kim,
JinAh Yoo,
SangHee Kim,
Seung M Shin,
Youn S Lee,
Soo Y Hur,
Yong W Kim,
Tae E Kim,
Yeun J Chung,
Shin S Jeun,
Dong W Kim,
Yong G Park,
Jin Kim,
Soon Y Shin,
Young H Lee, Jin W Kim
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ABSTRACT: Cell transdifferentiation is characterized by loss of some phenotypes along with acquisition of new phenotypes in differentiated cells. The differentiated state of a given cell is not irreversible. It depends on the up- and downregulation exerted by specific molecules.
We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell.
Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.
BMC Cell Biology 01/2010; 11:49. · 2.59 Impact Factor
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ABSTRACT: Tumor specimens obtained from 136 patients with primary carcinoma of the uterine cervix were analyzed for the presence of human papillomavirus (HPV) sequences and for mutation of the TP53 gene. Polymerase chain reaction (PCR) showed that 130 of 136 (96%) tumors contained an oncogenic HPV 16 or 18 sequence. HPV 16 was the predominant type in cervical squamous cell carcinomas and HPV 18 was significantly associated with cervical adenocarcinomas (p < 0.05). The more dedifferentiated the primary tumor, the more frequent the HPV 16 infection and the more differentiated, the more frequent the HPV 18 infection (p < 0.05). Two out of 136 (1.5%) tumors demonstrated single-strand conformation polymorphism (SSCP) band shifts. One (positive for HPV 18) had a nonsense mutation of codon 101 in exon 4 from AAA to TAA transversion. Another (positive for L1 consensus primer set) showed a point mutation involving codon 179 in exon 5 changing CAT to CGT transition. The three specimens negative for HPV did not contain TP53 gene mutations. Our data show that mutation of TP53 is infrequent in primary cervical carcinoma and there is no inverse correlation between HPV infection and TP53 gene mutation. Other mechanisms independent of TP53 inactivation may also be implicated in tumorigenesis of the uterine cervix.
07/2009; 36(3):295-300.
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ABSTRACT: In rats, oltipraz is metabolized via hepatic CYP1A1/2, 2B1/2, 2C11, 2D1/2, and 3A1/2, and omeprazole via hepatic CYP1A1/2, 2D1/2, and 3A1/2. Hence, pharmacokinetic interaction between oltipraz and omeprazole were evaluated after simultaneous single i.v. and p.o. administration of both drugs to rats. After i.v. administration of oltipraz (10 mg/kg) and omeprazole (20 mg/kg), the AUC of both drugs was significantly greater (32.3 and 28.1% increase for oltipraz and omeprazole, respectively) than those after each drug alone. This could have been due to a competitive inhibition of metabolism of oltipraz by omeprazole via CYP1A1 and 3A2, and of metabolism of omeprazole by oltipraz via CYP1A1/2, 2D1/2, and 3A1/2. This could be supported by the apparent inhibition constants (K(i)) and the concentrations of each drug in the liver. After oral administration of oltipraz (30 mg/kg) and omeprazole (40 mg/kg), the AUC of oltipraz was significantly greater (68.8% increase) than that after oltipraz alone. This could have been primarily due to an inhibition of intestinal metabolism of oltipraz by omeprazole. However, comparable AUC values of omeprazole between p.o. administration of omeprazole alone and both drugs could have been due to insufficient inhibitory effect of oltipraz on omeprazole metabolism in both the liver and intestine.
European Journal of Pharmaceutical Sciences 01/2008; 32(4-5):328-39. · 3.21 Impact Factor
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ABSTRACT: Pharmacokinetic parameters of oltipraz were compared after intravenous (10 mg/kg) and oral (50 mg/kg) administration to control male Sprague-Dawely rats and mutant Nagase analbuminemic rats (NARs). In NARs, the expression and mRNA level of CYP1A2 increased, and oltipraz was mainly metabolized via CYP1A1/2, 2B1/2, 2C11, 201, and 3A1/2 in male rats. Hence, it may be expected that the CL of oltipraz would be significantly faster in NARs. This was proven by the following results. After intravenous administration, the CL of oltipraz was significantly faster in NARs (125% increase) than controls due to significantly greater free fractions (unbound to plasma proteins) of oltipraz (197% increase) and significantly faster CL(int) for the disappearance of oltipraz (11.4% increase) in NARs, since oltipraz is an intermediate hepatic extraction ratio drug in rats. The V(ss) was significantly larger in NARs (109% increase) and this could be due to significant increase in free fractions of oltipraz in NARs. After oral administration, the AUC of oltipraz was also significantly smaller in NARs (61.9% decrease). This could also be due to significant increase in free fractions of oltipraz and significantly faster CL(int) in NARs. However, this was not due to decrease in absorption in NARs.
Journal of Pharmaceutical Sciences 06/2006; 95(5):998-1005. · 3.06 Impact Factor
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ABSTRACT: Pharmacokinetics and therapeutic effects of oltipraz were evaluated after consecutive (once per day at 30 mg/kg/day for 7 and 14 days) or intermittent (once per week at 100 mg/kg/week for 1-3 weeks) oral administration to rats with liver cirrhosis induced by dimethylnitrosamine. The AUC of oltipraz was significantly greater in cirrhotic rats than controls (890 compared with 270 microg . min/mL) due to impaired liver function in cirrhotic rats. However, the AUC values after consecutive 7 (421 compared with 753 microg . min/mL) and 14 (309 compared with 821 microg . min/mL) days oral administration of oltipraz in cirrhotic rats were significantly smaller than those in respective vehicle-treated cirrhotic rats. Moreover, the AUC values after intermittent 2 and 3 weeks in cirrhotic rats were also significantly smaller than that in 1 week vehicle-treated cirrhotic rats (2370 and 1690 compared with 4760 microg . min/mL). This could be due to induction of CYP isozymes and considerably greater numbers of normal liver cells in cirrhotic rats by oral administration of oltipraz. Improved liver function by oltipraz in cirrhotic rats was proved by liver microscopy; livers are free of significant fibrosis, although evidence of bridging necrosis is still present in many rats.
Journal of Pharmaceutical Sciences 06/2006; 95(5):985-97. · 3.06 Impact Factor
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ABSTRACT: Effects of cysteine on the pharmacokinetics of oltipraz were investigated after iv (10 mg/kg) and oral (30 mg/kg) administration to male control, protein-calorie malnutrition (PCM), and PCM with oral cysteine supplementation (PCMC) rats. It was reported that oltipraz was mainly metabolized via hepatic CYP1A1/2, 2B1/2, 2C11, 3A1/2, and 2D1 in male rats. The expression and mRNA levels of CYP1A2, 2C11, and 3A1/2 were also reported to decrease in male PCM rats compared with controls. Interestingly, the decreased CYP isozymes in PCM rats returned fully or partially to controls by oral cysteine supplementation (PCMC rats). Hence, it would be expected that in PCM rats, some pharmacokinetic parameters of oltipraz are fully or partially returned to controls by cysteine. This was proven by the following parameters in PCMC rats: the AUC (328, 782, and 416 mug min/mL for control, PCM, and PCMC rats, respectively, after iv administration, and 223, 456, and 242 mug min/mL after oral administration), terminal half-life (130, 212, and 143 min), mean residence time (MRT) (149, 299, and 189 min), and in vitro CL(int) (0.181, 0.107, and 0.153 mL/min/mg protein) were fully returned to controls, and CL and CL(NR) values were partially returned to controls.
Journal of Pharmaceutical Sciences 08/2005; 94(7):1484-93. · 3.06 Impact Factor
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ABSTRACT: It was reported that the mean value of the extent of absolute oral bioavailability (F) of oltipraz at a dose of 20 mg/kg was 41.2% and only 2.68% of the oral dose was unabsorbed from the gastrointestinal tract in rats. Hence, the low F in rats could be due to considerable first-pass (gastric, intestinal and hepatic) effects. Hence, the first-pass effects of oltipraz were measured after intravenous, intraportal, intragastric and intraduodenal administration of the drug at a dose of 20 mg/kg to rats. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values between intragastric and intraduodenal administration (213 and 212 microg min/ml) in rats were almost similar, but the values were significantly smaller than that after intraportal administration (316 microg min/ml) in rats, indicating that gastric first-pass effect was almost negligible (due to negligible absorption of oltipraz from rat stomach), but the intestinal first-pass effect of oltipraz was considerable, approximately 32% of the oral dose. The hepatic first-pass effect of oltipraz was approximately 40% based on AUC values between intravenous and intraportal administration (319 versus 536 microg min/ml). Since approximately 65% of the oral oltipraz was absorbed into the portal vein, the value of 40% was equivalent to 25% of the oral dose. The low F of oltipraz in rats was mainly due to considerable hepatic and intestinal first-pass effects.
Biopharmaceutics & Drug Disposition 06/2005; 26(4):129-34. · 2.07 Impact Factor
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ABSTRACT: Dose-independent pharmacokinetics of oltipraz after intravenous and/or oral administration at various doses to mice, rats, rabbits and dogs were evaluated. After both intravenous and/or oral administration of oltipraz to mice (5, 10 and 20 mg/kg for intravenous and 15, 30 and 50 mg/kg for oral administration), rats (5, 10 and 20 mg/kg for intravenous and 25, 50 and 100 mg/kg for oral administration), rabbits (5, 10 and 30 mg/kg for intravenous administration) and dogs (5 and 10 mg/kg for intravenous and 50 and 100 mg/kg for oral administration), the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of oltipraz were dose-proportional in all animals studied. Animal scale-up of some pharmacokinetics parameters of oltipraz was also performed based on the parameters after intravenous administration at a dose of 10 mg/kg to mice, rats, rabbits and dogs. Linear relationships were obtained between log time-averaged total body clearance (Cl) x maximum life-span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r=0.999; p=0.0015), log Cl (l/h) and log W (kg) (r=0.979; p=0.0209), and log apparent volume of distribution at steady state (V(ss)) (l) and log W (kg) (r=0.999; p=0.0009). The corresponding allometric equations were ClxMLP=49.8 W(0.861), Cl=5.20 W(0.523) and V(ss)=4.46 W(0.764). Interspecies scale-up of plasma concentration-time data for the four species using pharmacokinetic time of dienetichron resulted in similar profiles. In addition, concentrations of oltipraz in a plasma concentration-time profile for humans predicted using the four animal data fitted to the dienetichron time transformation of animal data.
Biopharmaceutics & Drug Disposition 05/2005; 26(3):99-115. · 2.07 Impact Factor
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ABSTRACT: Pharmacokinetic parameters of oltipraz were compared after intravenous and oral administration at a dose of 30 mg/kg to control rats and rats with water deprivation for 72 h (rats with dehydration). The plasma protein binding of oltipraz was measured in both groups of rats using an equilibrium dialysis technique. The concentrations of oltipraz were measured by the reported HPLC analysis. After intravenous administration, the total area under the plasma concentration-time curve from time zero to time infinity (AUC), terminal half-life, time-averaged total body and nonrenal clearances, and apparent volume of distribution at steady state were not significantly different between the two groups of rats. However, after oral administration to rats with dehydration, the AUC was significantly smaller than that in control rats (180 versus 316 microg min/ml) mainly due to decrease in absorption. In rats with dehydration, plasma protein binding was significantly greater than that in control rats (91.5 +/- 0.309 versus 81.3 +/- 2.79%).
Biopharmaceutics & Drug Disposition 04/2005; 26(2):77-83. · 2.07 Impact Factor
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ABSTRACT: Pharmacokinetic parameters of oltipraz were compared after intravenous and oral administration at a dose of 30 mg/kg to control rats and rats with U-ARF. After intravenous administration to rats with U-ARF, the AUC was significantly greater (1100 versus 1730 microg x min/mL) than that in control rats, and this could be due to significantly slower CL (27.2 versus 17.3 mL/min/kg). The slower CL could be mainly due to significantly slower CL(NR) (27.2 versus 17.3 mL/min/kg), and this could be supported by significantly slower in vitro CL(int) (32.1 versus 13.2 mL/min/whole liver) in the rats. The Vss was significantly larger in rats with U-ARF (4050 versus 5680 mL/kg), and this was not due to a significant increase in free fractions (unbound in plasma proteins) of oltipraz in the rats because the free fractions were 17.0 and 15.7% for control rats and rats with U-ARF, respectively. Unexpectedly, after oral administration to rats with U-ARF, the AUC of oltipraz was significantly smaller than that in control rats (329 versus 149 microg x min/mL), and this could be mainly due to a decrease in the absorption of oltipraz from the gastrointestinal tract in the rats (95 and 72% of the oral dose were absorbed in control rats and rats with U-ARF, respectively).
Journal of Pharmaceutical Sciences 10/2004; 93(9):2353-63. · 3.06 Impact Factor
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Tae E Kim,
Yong W Kim,
Seung Y Hwang,
Seung M Shin,
Jin W Shin,
Young H Lee,
Sun Y Shin,
Ku T Han,
Joon M Lee,
Sung E Namkoong, Jin W Kim
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ABSTRACT: To identify the genes involved in cervical carcinogenesis, we applied the mRNA differential display method and identified a candidate tumor suppressor gene, HCCS-1, which was present in normal cervical tissue but absent in cervical cancer, metastatic lymph node and CUMC-6 cervical cancer cell line. HCCS-1 transcripts were expressed in many normal tissues including leukocyte, lung, spleen, liver, heart and uterine cervix. Its expression was absent in 8 human cancer cell lines. HCCS-1-transfected HeLa cells exhibited growth inhibition by about 50%. This inhibitory effect of HCCS-1 on cervical cancer cells was associated with apoptotic process including DNA fragmentation. HCCS-1-transfected HeLa cells were shown to release cytochrome c from mitochondria, which activates caspase-9 and -3 and finally results in cleavage of poly(ADP-ribose) polymerase. Apoptosis formation was detected by propidium-iodide/annexin V. HCCS-1-transfected HeLa cells were more sensitive to adriamycin or UVC ray triggered apoptosis. These results suggest that HCCS-1 is downregulated in multiple human tumor types and may serve as a candidate tumor suppressor gene through apoptotic pathway against human cervical cancer.
International Journal of Cancer 03/2002; 97(6):780-6. · 5.44 Impact Factor
