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Morito Monden

Publications and source records attributed to Morito Monden.

At least 163 records · Page 9Linked to original sources
PubMed2003

Experimental study to evaluate the usefulness of S-1 in a model of peritoneal dissemination of gastric cancer.

BACKGROUND: Favorable results have been reported for the novel oral anticancer agent S-1 (TS-1) in clinical studies of advanced gastric cancer with peritoneal dissemination. In the present study we assessed its pharmacokinetics, inhibitory effects, and effect on survival time in an animal model. METHODS: A model of peritoneal dissemination was created by intraperitoneally implanting 4-week-old female BALBc nu/nu mice with the human gastric cancer cell line MKN-45 after transfection with a fluorescent protein-expressing vector. Pharmacokinetics were investigated by measuring intratumor, peritoneal lining, and blood concentrations after the administration of S-1 and fluorouracil (5-FU). The effect of S-1 on survival time was also assessed, by administration once daily to seven animals per group, starting on day 7 after implantation, and survival time was compared with that of an untreated control group. The inhibitory effect of S-1 on peritoneal dissemination was evaluated by killing mice at the start of administration, and 1 and 3 weeks after the start of administration, and examining them for the presence of peritoneal dissemination under a fluorescence stereomicroscope. RESULTS: Maintenance of high 5-FU concentrations in the intraperitoneal tumors was confirmed in the S-1 group, and survival time was prolonged without any decrease in oral food intake or body weight. CONCLUSION: Assessment in a model of peritoneal dissemination of gastric cancer showed that the novel oral anticancer agent S-1 was effective against peritoneal dissemination, and that it improved the survival rate.

Animals↗
PubMed2003

Absence of beta-tubulin gene mutation in gastric carcinoma.

BACKGROUND: Effective chemotherapy for advanced gastric cancer is yet to be established. Taxanes, novel anticancer drugs which bind to beta-tubulin and prevent disruption of microtubules, are newly approved and promising agents for advanced and recurrent gastric cancer. To predict the chemoresistance to a taxan in gastric cancer, we examined the genetic mutations of the beta-tubulin gene. METHODS: Fifty pairs of gastric tumor and normal mucosa tissues were obtained from operations and the genomic DNA was extracted from each specimen. The four exons of the beta-tubulin gene were amplified for DNA mutations by single-strand conformation polymorphism (SSCP) methods and sequencing analysis. RESULTS: Nine (18%) of 50 patients with gastric cancer had two kinds of silent variations of the beta-tubulin gene in exon 4. Three kinds of intronic variations were detected in exons 1, 2, and 3. However, no genetic alterations that would change the beta-tubulin protein structure were detected in any of the 50 gastric tumors. CONCLUSION: Our findings indicate that mutations of the beta-tubulin gene, which might be a contraindication for chemotherapy based on taxans, were very rare events in gastric cancer.

Aged↗
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

A high endothelial venule-expressing promiscuous chemokine receptor DARC can bind inflammatory, but not lymphoid, chemokines and is dispensable for lymphocyte homing under physiological conditions.

Chemokines displayed on the luminal surface of blood vessels play pivotal roles in inflammatory and homeostatic leukocyte trafficking in vivo. However, the mechanisms underlying the functional regulation of chemokines on the endothelial cell surface remain ill-defined. A promiscuous chemokine receptor, the Duffy antigen receptor for chemokines (DARC), has been implicated in the regulation of chemokine functions. Here we show that DARC is selectively expressed at the mRNA and protein levels in the high endothelial venules (HEV) of unstimulated lymph nodes (LN). To examine the biological significance of DARC expression in HEV, we performed competitive binding experiments with 20 different chemokines. The results showed that DARC selectively bound distinct members of the pro-inflammatory chemokines such as CXCL1, CXCL5, CCL2, CCL5 and CCL7, but not lymphoid chemokines such as CCL21, CCL19, CXCL12 and CXCL13 that are normally expressed in HEV. CCL2 bound to DARC failed to induce a significant cytosolic [Ca(2+)] elevation in CCR2B-expressing cells, whereas the free form of CCL2 induced a distinct [Ca(2+)] elevation, suggesting that DARC down-regulates activities of pro-inflammatory chemokines upon binding. Targeted disruption of the gene encoding DARC did not induce any obvious changes in the cell number or leukocyte subsets in the peripheral and mesenteric LN. Neither did DARC deficiency significantly affect lymphocyte migration into LN. These results suggest that DARC may be a scavenger for pro-inflammatory chemokines, but not a presenting molecule for lymphoid chemokines at HEV and that it is probably functionally dispensable for lymphocyte trafficking to HEV-bearing lymphoid tissues under physiological conditions.

Animals↗
PubMed2003

Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma.

Expression of the Wilms' tumor gene WT1 was examined in 59 cases of colorectal adenocarcinoma to examine the involvement of WT1 in tumorigenesis. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) showed that WT1 mRNA was expressed in the range from 7.2 x 10(-5) to 4.9 x 10(-1) levels (WT1 expression level in K562 leukemic cells was defined as 1.0) in all (100%) of the 28 cases of colorectal adenocarcinoma examined, and that the WT1 mRNA expression levels were higher in 20 (71%) of the 28 cases compared to those of normal-appearing mucosal tissues examined. Immunohistochemical analysis using an anti-WT1 antibody was performed on 46 cases of colorectal adenocarcinoma (15 of the 28 cases with WT1 mRNA expression and 31 newly collected cases), and the expression of WT1 protein was detected in 41 (89%) of the 46 cases. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of the 10 exons of the WT1 gene in any of 5 different colorectal adenocarcinomas. These results may indicate an important role of the wild-type WT1 gene in tumorigenesis of colorectal adenocarcinoma.

Adenocarcinoma↗
PubMed2003

Prevention of peritoneal metastasis of human gastric cancer cells in nude mice by S-1, a novel oral derivative of 5-Fluorouracil.

OBJECTIVE: Recent clinical trials have suggested that oral administration of a new anti-cancer agent, S-1, seems a promising therapy for advanced gastric cancer. In this study, we assessed the efficacy of S-1 against peritoneal dissemination of gastric cancer in a newly developed animal model and investigated the efficacy of S-1 from a pharmacokinetic angle. METHODS: Human gastric cancer cells (MKN-45) were injected into the peritoneal cavity of nude mice. The cancer cells were transduced using an enhanced green fluorescent protein (EGFP)-expressing plasmid vector, enabling micrometastatic foci to be accurately assessed with a high level of detection sensitivity. To investigate pharmacokinetics, the concentration of 5-FU was determined in tumor, peritoneum and plasma. RESULTS: Fourteen and 21 days after intraperitoneal injection, a significant difference in the number of fluorescent foci was observed between the control group and the S-1 group (p = 0.02 and p = 0.0024, respectively. The therapeutic effect of S-1 was significantly greater than that of 5-FU. Furthermore, S-1 treatment greatly improved the survival time and cachexia. The area under the curve of 5-FU in tumor was higher than in the peritoneum and plasma. CONCLUSION: Oral S-1 is a promising chemotherapy for peritoneal dissemination of gastric cancer.

Administration, Oral↗
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↗
PubMed2003

Quantitative molecular diagnosis of peritoneal lavage fluid for prediction of peritoneal recurrence in gastric cancer.

We developed a quantitative multiple-marker RT-PCR assay for sensitive detection of free cancer cells in the peritoneal cavity and examined the significance of this molecular diagnostic technique for detection and prediction of peritoneal dissemination in patients with gastric cancer. Preoperative peritoneal lavage fluid samples obtained from 129 patients with gastric cancer were subjected to RT-PCR assay with primers specific for carcinoembryonic antigen (CEA) and cytokeratin-20 (CK-20), and conventional cytological examination with Papanicolaou staining. The multi-marker RT-PCR assay was positive in 59 of 129 (46%) gastric cancer patients, whereas conventional cytology was positive in only 9 of 129 (7%) patients. Thirty-two of 129 (22%) patients suffered disease recurrence after surgery. Twenty-one of these patients were confirmed to have had peritoneal recurrence. Although conventional cytology was positive on peritoneal washes in only 9 patients, the RT-PCR assay was positive in 20 of these 21 patients. Furthermore, in cases with negative cytology, patients with PCR-positive findings in peritoneal lavage fluid had a significantly poorer prognosis than those with negative PCR, mainly because of peritoneal recurrence. Our results suggest that the multiplex RT-PCR assay for CEA and CK-20 was highly sensitive for detection and might be useful for prediction of peritoneal dissemination in gastric cancer.

Ascitic Fluid↗
PubMed2003

[A case of liver metastasis of pancreatic duct carcinoma successfully treated with gemcitabine].

We report a patient in whom systemic chemotherapy using gemcitabine was effective against liver metastases of pancreatic cancer. A 72-year-old woman underwent pancreatoduodenectomy with lymphadenectomy and partial resection of the portal vein following a diagnosis of pancreatic cancer, and her postoperative course was uneventful. The diagnosis was stage III anaplastic ductal carcinoma (t2n1P0H0M0). One year and 3 months after the operation, however, her serum level of carbohydrate antigen 19-9 (CA19-9) was found to be elevated, and CT examination revealed a mass in the liver that was diagnosed as liver that was metastases. Systemic chemotherapy was performed with a regimen of gemcitabine 600 mg/m2/week for 3 weeks, followed by a week rest, for the first three courses. On and after fourth course, gemcitabine 1,000 mg/m2/week was administered. The serum CA19-9 level was down from 882 U/ml to normal after 5 courses of chemotherapy and CT examination revealed that liver metastases had completely vanished. Although no evidence of deterioration was observed, the patient died of infectious pneumonia 10 months after recurrence. The prognosis of liver metastases of pancreatic cancer is quite unfavorable. However, if remission is achieved with gemcitabine, the patient has the possibility to obtain a better outcome.

Aged↗
PubMed2003

Association of BRCA2 polymorphism at codon 784 (Met/Val) with breast cancer risk and prognosis.

PURPOSE: The association of BRCA2 polymorphisms at codon 372 [Asn (N)/His (H)]and codon 784 [Met (M)/Val (V)] with breast cancer risk was evaluated in Japanese women. In addition, the prognostic significance of these polymorphisms was studied in breast cancer patients. EXPERIMENTAL DESIGN: A case-control study was conducted to examine the association of the BRCA2 N/H372 polymorphism and M/V 784 polymorphism with breast cancer risk (cases = 149, controls = 154). The prognostic significance of these polymorphisms was evaluated in 139 patients with primary breast cancer. RESULTS: No significant association was observed between the N/H372 polymorphism and breast cancer risk. In contrast, a significant increase in breast cancer risk (odds ratio, 2.03; 95% confidence interval, 1.07-3.87) was observed in carriers of the variant allele (V784) of the M/V784 polymorphism as compared with noncarriers after adjustment for the classical risk factors, age, family history, parity, body mass index, and so forth. Among breast cancer patients, various clinicopathological parameters including menopausal status, tumor size, lymph node status, histological grade, and estrogen-receptor status were not significantly different between the carriers and noncarriers of the variant allele with regard to both N/H372 and M/V784 polymorphisms. The N/H 372 polymorphism was not significantly associated with patient prognosis. On the other hand, breast cancer patients carrying the variant allele of M/V784 polymorphism showed a significantly (P = 0.014) lower 3-year disease-free survival rate (63%) than noncarriers (92%). Multivariate analysis has revealed that the M/V784 polymorphism is a significant prognostic factor, being independent of the other conventional prognostic factors such as lymph node status and estrogen receptor status. CONCLUSION: These results suggest that the M/V784 polymorphism, but not the N/H372 polymorphism, would be useful in the selection of women at high risk for developing breast cancer and would also serve as a clinically useful prognostic factor in breast cancer patients.

Alleles↗
PubMed2003

Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas.

PURPOSE AND EXPERIMENTAL DESIGN: CDC25 genes are cell cycle-activating phosphatases that positively regulate the activity of cyclin-dependent kinase. CDC25A and CDC25B, being oncogenes, are overexpressed in a variety of human malignancies. To investigate the potential roles of CDC25s in hepatocellular carcinoma (HCC), expression of CDC25A and CDC25B was examined in human HCC samples. RESULTS: Reverse transcription-PCR showed that overexpression of CDC25A and CDC25B mRNAs was found in 9 of 13 (69%) and 4 of 13 (31%) HCCs, respectively. Immunohistochemistry of 59 HCCs showed marked increase in CDC25A expression, but not CDC25B, in HCC compared with noncancer tissues, and high expression of CDC25A in 33 of 59 (56%) HCCs. Overexpression of CDC25A in HCC was confirmed by Western blot analysis. High expression of CDC25A was associated with dedifferentiated phenotype and portal vein invasion (P = 0.001 and 0.031, respectively), and expression of CDC25A correlated well with proliferating cell nuclear antigen labeling index (P = 0.005). Univariate analysis indicated that high expression of CDC25A and proliferating cell nuclear antigen were both significant predictive factors for shorter disease-free survival (P = 0.004 and 0.039, respectively). Multivariate analysis indicated that CDC25A was an independent prognostic marker for disease-free survival (risk ratio for cancer relapse, 2.98; P = 0.029), even when analyzed with several clinicopathologic factors. On the other hand, expression of CDC25B did not correlate with any clinicopathological features. CONCLUSION: Our findings suggest that CDC25A, but not CDC25B, could be used as an independent prognostic marker for HCC. Our data would also contribute to forward understanding of tumor biology of HCC that is associated with cell cycle regulation.

Adult↗
PubMed2003

Growth inhibition of pancreatic cancer cells through activation of peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha pathway.

Peroxisome proliferator-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. Though previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of certain types of cancer cells, little is known about the growth inhibitory effects mediated though activation of PPARgamma/RXRalpha. We examined the effects of troglitazone (one type of TZDs) and 9-cis retinoic acid, a RXRalpha ligand, on activation of PPARgamma/RXRalpha and growth inhibition of human pancreatic cancer cell lines (AsPC1, BxPC3, PSN1, PCI6, Panc1, KMP-4, and KMP-7). Combined treatment of troglitazone and 9-cis retinoic acid showed enhanced transcriptional activity and enhanced antiproliferative effects. In PSN1 cells, G1 cell cycle arrest and apoptosis were induced by troglitazone and these effects were enhanced with additional 9-cis RA. Our findings suggest that activation of PPARgamma/RXRalpha pathway might play an important role in growth inhibition of pancreatic cancer cells via G1 cell cycle arrest and apoptosis. This nuclear receptor might be a suitable molecular target for treatment of pancreatic cancers.

Alitretinoin↗