Biomedical subjects

Masato Sakon

Publications and source records attributed to Masato Sakon.

At least 73 records · Page 4Linked to original sources

PubMed2004

[Influence on 5-fluorouracil metabolism by combination of interferon-alpha and 5-fluorouracil against human hepatocellular carcinoma xenografts].

To investigate the effect of biochemical modulation on antitumor activity shown by the combination of 5-Fluorouracil (5-FU) and interferon-alpha (IFN-alpha), experimental therapy was performed on human hepatocellular carcinoma cell (HuH7, PLC/PLF/5) xenografts inoculated into nude mice, using 5-FU and IFN-alpha, either alone or in combination. These agents showed antitumor activity in different degrees. Although IFN-alpha, given as 100,000 units/mouse/3 times/week subcutaneously x 6, and 5-FU, given as 0.5 mg/mouse/3 times/week intraperitoneally, showed addititive antitumor effect against HuH7 and PLC/PLF/5, the activities of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), uridine phosphorylase (UP) and uridine kinase (UK) were not significantly influenced in the tumors treated with the 5-FU/IFN-alpha combination, compared with those treated with 5-FU or IFN-alpha alone. This suggested that antitumor activity of 5-FU and IFN-alpha in combination was not significantly involved in 5-FU metabolism in two human hepatocellular carcinoma cell lines examined.

Animals↗

PubMed2004

[A case of successful treatment with combined 5-fluorouracil, adriamycin, cisplatin (FAP) therapy followed by Gemcitabine, UFT therapy and intra-arterial FAP therapy for unresectable advanced gallbladder cancer].

The prognosis of unresectable advanced gallbladder cancer is extremely poor. We presented a 61-year-old female with unresectable advanced gallbladder cancer who received FAP therapy, Gemcitabine + UFT therapy, and an intra-arterial FAP therapy that followed. She is still alive 18 months after the first diagnosis. It may be possible to improve the prognosis by maintaining QOL using the combination of chemotherapies such as FAP, Gemcitabine, and UFT.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

[Successful treatment for advanced cholangiocellular carcinoma with intrahepatic metastasis and/or portal vein tumor thrombi by intraarterial chemotherapy combined with 5-fluorouracil, adriamycin and cisplatin (FAP)--two cases report].

The patients of unresectable cholangiocellular carcinoma (CCC) have extremely poor prognosis. Case 1 was a 72-year-old male who had CCC in the left lobe of liver with intrahepatic metastasis. From June 2003, he received hepatic arterial infusion chemotherapy (FAP: 5-fluorouracil 250 mg/day continuous infusion, day 1-5, adriamycin 10 mg/day, day 1, and CDDP 10 mg/day, day 1). After 5 courses, abdominal CT revealed that the main tumor had regressed. Case 2 was a 66-year-old male who had CCC with portal vein tumor thrombus of anterior branch (Vp2). He received FAP arterial infusion chemotherapy that was a same regimen as with the case 1 patient. After 5 courses were administered, Abdominal CT revealed that the size of the main tumor at S8 had not changed, and that portal vein tumor thrombus had disappeared. In both cases, there was no complication related to the chemotherapy. They are alive for more than 1 year after chemotherapy had started. FAP hepatic arterial infusion chemotherapy might be promising as an effective therapy for non-resectable CCC without extra hepatic metastasis.

Aged↗

PubMed2004

[A case of long-term survivor with multiple pulmonary metastases of HCC after hepatic resection].

A 52-year-old male was admitted to our hospital with huge hepatoma of the right lobe. He underwent a right lobectomy of the liver in July 1999. After five months from the surgery, multiple recurrences in the liver and lung were revealed with Computed tomography (CT). TAE was performed for intrahepatic recurrence and a combination therapy, consisting of UFT and interferon-alpha, was started for pulmonary metastasis. Then 5-FU/CDDP/interferon-alpha therapy was given in 2001 and TS-1/interferon-beta therapy was given thereafter in 2002. Consequently, the patient survived for 31 months with no disturbance in quality of life. No intrahepatic recurrence was also detected during the survival period. It was suggested that a good prognosis may be expected, even in the HCC case with distant metastasis after hepatic resection, if the primary cite was curatively treated.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Thiazolidinediones inhibit growth of gastrointestinal, biliary, and pancreatic adenocarcinoma cells through activation of the peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha pathway.

Peroxisome prolixferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Although previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of several types of tumor cells, the precise mechanism still remains obscure. The present study was designed to examine the effects of PPARgamma/RXRalpha transcriptional activation on cell growth in cancer cells. We compared the effects of six types of TZDs (troglitazone, RS-1303, RS-1330, RS-1387, RS-1455, and RS-1456) and 9-cis RA, an RXRalpha ligand, on the activation of PPARgamma/RXRalpha and the growth inhibition of six types of adenocarcinoma cell lines (MKN45, HT-29, HCT116, HuCCT1, KMP-2, and BxPC3) established from abdominal malignancies. PPARgamma was expressed in all six tumor cell lines and transcriptionally functional in five of the six lines. The stronger PPARgamma activator showed the stronger growth inhibitor in these five cell lines. However, no significant growth inhibitory effect of six types of PPARgamma activators was observed in BxPC3 cells, which showed no significant PPARgamma transactivation by these activators. Simultaneous addition of troglitazone and 9-cis RA enhanced both activation of PPARgamma/RXRalpha and growth inhibition in several types of cancer cells. The degree of PPARgamma/RXRalpha activation correlated with the extent of growth inhibition (r > 0.70, P < 0.05). This growth inhibition was associated with G1 cell cycle arrest and cell differentiation. These findings suggest that activation of the PPARgamma/RXRalpha pathway plays an important role in the growth inhibition of tumor cells and that this nuclear hormone receptor may be a possible novel molecular target for treatment of tumors in humans.

Adenocarcinoma↗

PubMed2003

Expression level of valosin-containing protein is strongly associated with progression and prognosis of gastric carcinoma.

PURPOSE: Valosin-containing protein (VCP; also known as p97) was shown to be associated with antiapoptotic function and metastasis via activation of nuclear factor kappa-B signaling pathway. In this study, association of VCP expression with recurrence of gastric carcinoma (GC), in which lymphatic vessels are the main route of spread, was examined. PATIENTS AND METHODS: VCP expression in 330 patients with GC (242 males and 88 females) with ages ranging from 26 to 81 years (median, 60 years) was analyzed by immunohistochemistry, in which staining intensity in tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. RESULTS: Ninety-four (28.7%) patient cases showed level 1 and 233 patient cases (71.3%) showed level 2 VCP expression. Patients with level 2 expression showed higher rates of large tumor size (P <.0001), undifferentiated histologic subtype (P <.05), presence of vascular and lymphatic invasion (P <.0001 for both), presence of lymph node metastasis (P <.0001), deep tumor invasion (P <.0001), and poorer disease-free and overall survivals (P <.0001 for both) compared with those with level 1 VCP expression. Multivariate analysis revealed VCP expression level as an independent prognosticator for disease-free and overall survival. VCP level was an indicator for disease-free and overall survival in the early (pT1; P <.01 and P <.05, respectively) and advanced (pT2-4; P <.05 for both) group of pathologic tumor-node-metastasis system classification. CONCLUSION: The prognostic significance of VCP expression level in GC was demonstrated.

Adenosine Triphosphatases↗

PubMed2003

Living-related liver transplantation with renoportal anastomosis for a patient with large spontaneous splenorenal collateral.

BACKGROUND: A large splenorenal collateral must be interrupted during liver transplantation to secure adequate portal perfusion. However, this process increases the complexity of the operative procedure and may cause hazardous bleeding. Recently, renoportal anastomosis in portal reconstruction was reported in cadaveric liver transplantation for patients with surgically created splenorenal shunts. We used this technique in a living-related liver transplantation. METHODS: A 29-year-old female with a large spontaneous splenorenal collateral and a portal venous thrombus underwent a living-related liver transplantation. At surgery, the left renal vein was divided and the distal stump was anastomosed to the portal vein of the graft without interrupting collaterals. RESULTS: Adequate portal venous blood flow was maintained throughout the postoperative course. The patient was discharged 9 weeks after transplantation and remains well. CONCLUSION: The renoportal anastomosis could be used for portal reconstruction in living-related liver transplantation for patients with a large splenorenal collateral. It provides adequate portal perfusion without interrupting collateral circulation.

Adult↗

PubMed2003

Suppression of oxidative stress-induced hepatocyte injury by calpain antisense.

BACKGROUND: Calpain, a cytosolic Ca(2+)-dependent proteinase, plays a pivotal role in cell injury. In this study, we investigated the effect of calpain-mu antisense oligonucleotide on oxidative stress induced-hepatocyte injury. MATERIALS AND METHODS: Hemagglutinating virus of Japan liposome complex with one of three types of antisense oligonucleotide (AS-1, AS-2, AS-3) or scramble oligonucleotide was added to the culture medium of HuH7 cells and incubated for 6 days. The expression of calpain-mu protein was examined by Western blotting. After the addition of tert-butyl hydroperoxide, bleb formation was examined by phase contrast microscopy, and cell viability was assessed by the release of lactate dehydrogenase. RESULTS: Incubation of HuH7 cells with AS-2 resulted in a decrease in the amount of calpain on day 4 and a further decrease to almost undetectable levels on day 6, whereas scramble oligonucleotide had no effect. Bleb formation was observed 120 min after the addition of tert-butyl hydroperoxide in scramble oligonucleotide-treated cells as in untreated cells. In contrast, it was rarely observed in AS-2-treated cells. Lactate dehydrogenase release was significantly suppressed in AS-2-treated cells, compared with that in scramble oligonucleotide treated-cells. CONCLUSIONS: Our findings suggest that calpain activation is involved in the pathogenesis of oxidative stress injury and that transfection of calpain antisense may potentially protect against ischemia/reperfusion liver injury.

Calpain↗

PubMed2003

Elevated expression of valosin-containing protein (p97) in hepatocellular carcinoma is correlated with increased incidence of tumor recurrence.

PURPOSE: Valosin-containing protein (VCP; also known as p97) has been shown to be associated with antiapoptotic function and metastasis via activation of the nuclear factor-kappaB signaling pathway. In this study, association of VCP expression with recurrence of hepatocellular carcinoma (HCC) and patient survival was examined. PATIENTS AND METHODS: VCP expression in 170 patients (139 male and 31 female) with ages ranging from 31 to 81 years (median, 61 years) was analyzed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, in which staining intensity in tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. RESULTS: Immunohistochemically, 57 patients (35.2%) showed level 1, and 105 patients (64.8%) showed level 2, VCP expression. Quantitative RT-PCR analysis revealed higher VCP mRNA expression in level 2 patients (n = 7) than level 1 (n = 4) (P <.05). Patients with VCP-level 2 HCC showed higher rate of portal vein invasion in the tumor (P <.01) and poorer disease-free and overall survival (P <.0001 and P <.05, respectively) compared with level 1 patients. Multivariate analysis revealed VCP expression level, tumor multiplicity, and degree of fibrosis in the noncancerous liver tissue to be independent prognosticators for disease-free and overall survival. VCP level was an indicator for disease-free survival in each early- (I and II) and advanced- (III and IV) stage group of pathologic tumor-node-metastasis classification (P <.001 and P <.01, respectively). CONCLUSION: VCP expression level has prognostic significance for disease-free and overall survival of patients with HCC.

Adenosine Triphosphatases↗

PubMed2003

Gene transfer into the liver by plasmid injection into the portal vein combined with electroporation.

BACKGROUND: We investigated the optimum conditions for gene transfer into the liver by injection of plasmid via the portal vein combined with electroporation. METHODS: In anesthetized 7-week-old male Shionogi Wistar rats, a tapered 3Fr. catheter was inserted through a branch of the colonic vein and its tip was secured into the portal vein. After clamping the vessels around the right and caudal lobes of the liver, FITC-oligodeoxynucleotide (ODN), green fluorescence protein (GFP) plasmid, or pCAGGS-luciferase was injected into the right and caudal lobes during electroporation using electric pulses applied to the caudal lobe only. RESULTS: Transfected cells were identified by FITC-ODN and GFP fluorescence, and transfection efficacy was estimated by measurement of luciferase activity. FITC-ODN and GFP were detected in the caudal lobes of the liver. FITC-ODN was particularly present in hepatocytes surrounding the Glisson capsule and central veins, while GFP was detected in only hepatocytes surrounding the Glisson capsule. Luciferase activity in the liver was dependent on the plasmid concentration and voltage of the electric pulse, but independent of the volume of plasmid solution. Luciferase activity was limited in the right lobe, in which plasmid solution was injected but no electroporation was applied. CONCLUSIONS: Our results showed local expression of the induced gene at the electroporation site, suggesting it is potentially useful for liver function support during recovery after extensive liver surgery and for the treatment of chronic and/or diffuse liver diseases.

Animals↗

PubMed2003

Electroporation-mediated ex vivo gene transfer into graft not requiring injection pressure in orthotopic liver transplantation.

BACKGROUND: We investigated optimum conditions for ex vivo gene transfer into liver grafts by plasmid injection via the portal vein combined with electroporation in rat liver transplantation. METHODS: Anesthetized 9-week-old male Shionogi-Wistar rats were used as donors and recipients. After harvest of the liver graft from the donor rat, a tapered 3Fr. catheter was inserted into the portal vein of the liver graft ex vivo. After clamping the afferent vessels around the right and caudal liver lobes, pCAGGS-luciferase, which was diluted with one of several osmotic pressure solutions, or pCAGGS-green fluorescence protein (GFP) plasmid was injected into these lobes to keep the efferent vessels patent. Electrical pulses were applied to the liver graft during cold preservation in lactated Ringer's solution, University of Wisconsin solution, and histidine-tryptophan-ketoglutarate solution. RESULTS: Transfection efficacy was estimated by measurement of luciferase activity. Luciferase activity in the liver was dependent on both the voltage and electric current of the electrical pulse, and also on the type of preservation solution and plasmid osmotic pressure. Luciferase activity was noted only in plasmid-injected lobes of the liver graft. GFP-transfected cells were identified by GFP fluorescence. GFP was observed predominantly in perivascular cells, including hepatocytes. CONCLUSIONS: We have demonstrated successful ex vivo gene transfection into liver grafts without injection pressure by using a non-viral method.

Animals↗

PubMed2003

Patterns of regional lymph node involvement in intrahepatic cholangiocarcinoma of the left lobe.

Lymph node involvement is an important prognostic factor in intrahepatic cholangiocarcinoma. Besides the nodes in the hepatoduodenal ligament, recent studies have suggested that the nodes around the cardiac portion of the stomach or along the gastric lesser curvature can be affected when the primary tumor is located in the left hepatic lobe. However, the distribution of metastatic nodes has not been well described in this disease. Thirteen patients with intrahepatic cholangiocarcinoma in the left hepatic lobe were enrolled in this study. Lymphatic mapping was performed by means of both histologic examination and reverse transcriptase-polymerase chain reaction assays. Nodal involvement around the cardiac portion of the stomach or along the lesser gastric curvature (left pathway) was found in 7 (54%) of 13 patients by histologic examination or reverse transcriptase-polymerase chain reaction, whereas positive nodes in the hepatoduodenal ligament (right pathway) were found in 6 (46%) of 13 patients. Two patients (15%) had positive nodes only in the left pathway. Therefore, for a more accurate clinical staging of intrahepatic cholangiocarcinoma in the hepatic left lobe, lymph nodes around the cardiac portion of the stomach and along the lesser gastric curvature should be examined in addition to nodes in the hepatoduodenal ligament.

Adult↗

PubMed2003

JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis1.

BACKGROUND & AIMS: The aim of this study was to assess the effects of cyclooxygenase (COX)-2 inhibition on rat experimental liver fibrogenesis. METHODS: We investigated the inhibitory effects of a selective COX-2 inhibitor, JTE-522, on liver fibrosis induced by a choline-deficient, l-amino acid-defined diet (CDAA). Inhibitory effect was also tested in a second model of thioacetamide (TAA)-induced liver fibrosis. RESULTS: CDAA induced liver fibrosis and preneoplastic foci at 12 weeks and cirrhosis at 36 weeks. Hepatocellular carcinoma was noted in 13 of 15 rats (87%). JTE-522 significantly inhibited fibrosis and development of preneoplastic lesions in a dose-dependent manner and completely inhibited generation of cirrhosis and hepatocellular carcinoma at both low and high doses (10 and 30 mg/kg body wt/day, respectively). JTE-522 administrated only from 12 weeks to 36 weeks also prevented cirrhosis and formation of hepatocellular carcinoma. JTE-522 itself did not cause local or systemic gross or histopathologic changes at 36 weeks. Mechanistic studies indicated that the CDAA model displayed up-regulation of several biomarkers, including COX-2, arachidonate metabolite (prostaglandin E(2)), serum aspartate aminotransferase, and c-myc expression. The model also showed an increased proportion of activated hepatic stellate cells, proliferating cell nuclear antigen index, and CD45-positive inflammatory cells in the liver. JTE-522 effectively diminished these changes. JTE-522 exhibited similar antifibrosis effects in the TAA model. CONCLUSIONS: Our results suggest that COX-2 is involved in CDAA- and TAA-induced liver fibrosis. Our data also indicate that JTE-522 is a potent chemopreventive agent of rat liver fibrosis with low toxicity.

Actins↗

PubMed2003

Diagnosis of intrahepatic metastasis and multicentric carcinogenesis by microsatellite loss of heterozygosity in patients with multiple and recurrent hepatocellular carcinomas.

BACKGROUND/AIMS: The prognosis of hepatocellular carcinoma (HCC) is poor because of frequent intrahepatic metastasis (IM) or multicentric carcinogenesis (MC). We compared the effectiveness of loss of heterozygosity (LOH) analysis in the diagnosis of these two forms with that of histopathological diagnosis. METHODS: Using LOH analysis of 15 specific DNA microsatellite loci, tumor clonality was assessed in 37 cases. RESULTS: LOH was observed in 30% of seven solitary tumors. According to these results, the selected threshold to diagnose MC was a difference in the LOH status at more than 30% of the analyzed loci, when comparing two samples in the same liver. In nine multiple HCCs, identical genetic and histopathological diagnoses were found in four (IM: 2, MC: 2). Of 21 recurrent tumors, 19 showed LOH for at least one marker. IM and MC were genetically diagnosed in five and ten patients, respectively. Genetic and histopathological diagnoses were identical in ten of 19 patients (IM: 5. MC: 5). Five genetic MC were histopathologically diagnosed as IM (3) and 'undetermined' (2). CONCLUSIONS: Genetic diagnosis by LOH analysis may be more strict and specific than histopathological diagnosis in the differential diagnosis of IM and MC.

Adult↗

PubMed2003

Molecular features of non-B, non-C hepatocellular carcinoma: a PCR-array gene expression profiling study.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) usually develops following chronic liver inflammation caused by hepatitis C or B virus. Through expression profiling in a rare type of HCC, for which the causes are unknown, we sought to find key genes responsible for each step of hepatocarcinogenesis in the absence of viral influence. METHODS: We used 68 non-B, non-C liver tissues (20 HCC, 17 non-tumor, 31 normal liver) for expression profiling with PCR-array carrying 3072 genes known to be expressed in liver tissues. To select the differentially expressed genes, we performed random permutation testing. A weighted voting classification algorithm was used to confirm the reliability of gene selection. We then compared these genes with the results of previous expression profiling studies. RESULTS: A total of 220 differentially expressed genes were selected by random permutation tests. The classification accuracies using these genes were 91.8, 92.0 and 100.0% by a leave-one-out cross-validation, an additional PCR-array dataset and a Stanford DNA microarray dataset, respectively. By comparing our results with previous reports on virus-infected HCC, four genes (ALB, A2M, ECHS1 and IGFBP3) were commonly selected in some studies. CONCLUSIONS: The 220 differentially expressed genes selected by PCR-array are potentially responsible for hepatocarcinogenesis in the absence of viral influence.

Aged↗

PubMed2003

Noninvasive quantitative measurement of tissue blood flow in hepatocellular carcinoma using xenon-enhanced computed tomography.

The aim of this study was to quantitatively measure tissue blood flow (TBF) in hepatocellular carcinoma (HCC) by a noninvasive method using xenon (Xe) inhalation/CT scans and to correlate the measured TBF with histological features. TBF was measured in HCC with xenon-enhanced CT (xenon/CT) in 20 patients. In 15 patients with HCC diagnosed as hypervascular tumors by conventional CT, TBF of the tumors was significantly higher than that of noncancerous liver tissue (151.1 +/- 20 vs 42.6 +/- 20 ml/min/100 g). Histologically, these tumors were diagnosed as moderately-to-poorly differentiated HCC. In contrast, in five patients with hypovascular HCC, TBF of HCC was almost comparable to that of the noncancerous regions (45.3 +/- 6 vs 48.3 +/- 6 ml/min/100 g). All these tumors were well-differentiated HCC. In conclusions, the measured values of TBF correlate with the clinicopathologic features of liver tumors and nontumorous liver tissue in patients with HCC.

Administration, Inhalation↗

PubMed2003

Suppression of pancreatic cancer cell invasion by a cyclooxygenase-2-specific inhibitor.

Pancreatic cancer is characterized by invasive and metastatic potential. In this study, effects of the COX-2 inhibitor JTE-522 on cell viability, invasion, and invasion-related cellular properties were determined. JTE-522 (10 microM) induced a 75-90% reduction in invasion, compared to cells treated with a vehicle only, in the COX-2-expressing cells. In contrast, this inhibitor caused no significant reduction in cells lacking COX-2. Determinants of cell invasion, such as cell motility, adhesion to the extracellular matrix, and gelatinolytic activity of metalloproteinase, were also modulated in COX-2-positive pancreatic cancer cells. Thus, COX-2-specific inhibitors may be a useful anti-invasive therapeutic option in pancreatic cancer.

Benzenesulfonates↗

PubMed2003

Interferon-beta is more potent than interferon-alpha in inhibition of human hepatocellular carcinoma cell growth when used alone and in combination with anticancer drugs.

BACKGROUND: The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor, but promising effects of chemotherapies combined with interferon (IFN) have been reported. METHODS: To develop more effective combination therapies for HCC, we compared the antiproliferative effects of IFN-alpha and IFN-beta in combination with various cytotoxic drugs on hepatoma cell lines using MTT assay and isobologram analysis. RESULTS: IFN-beta was more potent than IFN-alpha in inhibiting the cell growth of all cell lines (P <.05, two-way ANOVA). PLC/PRF/5 was more sensitive to either IFN, than HLE and HuH7. Cell growth of all cell lines was inhibited in a dose-dependent manner by 5-fluorouracil (5-FU), cisplatin (CDDP), and doxorubicin (DOX), but the sensitivities of these cells were considerably different. As for IFN-alpha, synergistic effects were observed when combined with 5-FU and DOX on PLC/PRF/5 cells only, whereas IFN-beta showed synergistic effects with 5-FU and CDDP on HuH7 and PLC/PRF/5 cell lines. CONCLUSION: The spectra of the antiproliferative activity and synergistic effect of IFN-beta when combined with anticancer drugs are more potent than those of IFN-alpha. Combinations of IFN-beta and anticancer drugs may provide a better treatment of HCC when combinations with IFN-alpha are ineffective.

Analysis of Variance↗