Biomedical subjects

Yuji Takebayashi

Publications and source records attributed to Yuji Takebayashi.

31 records · Page 2Linked to original sources

PubMed2002

Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP.

Intrinsic or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with solid carcinoma. Cisplatin is one of the most effective chemotherapeutic agents for treating ovarian carcinoma. Recently, copper-transporting P-type adenosine triphosphatase (ATP7B) has been demonstrated as one of the genes responsible for cisplatin resistance in vitro. We hypothesized that the expression of ATP7B gene increases resistance to cisplatin in ovarian carcinoma and a priori knowledge of its expression is important for the choice of therapy. The aim of our study was to assess the role of ATP7B gene in ovarian carcinoma and compare its expression with those of multidrug resistance-related transporters such as MDR1, MRP1, MRP2, LRP and BCRP genes. The transporters' gene expression profiles from 82 patients treated with cisplatin-based chemotherapy after surgery were assessed by RT-PCR. We did not observe any significant correlation between ATP7B gene expression and those of MDR1, MRP1, MRP2, LRP or BCRP. The expression level of ATP7B gene was significantly increased (p < 0.05) in patients with moderately-/poorly-differentiated ovarian carcinomas treated with cisplatin-based chemotherapy, thus ATP7B may serve as an independent prognostic factor in these patients. In contrast, the expression level of MDR1, MRP1, MRP2, LRP and BCRP genes were not prognostic indicators of disease. These findings suggest that ATP7B gene may be considered as a novel chemoresistance marker and that inhibitor(s) of ATP7B might be useful, in patients with ovarian carcinoma treated with cisplatin-based chemotherapy.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2002

Uridine phosphorylase is a potential prognostic factor in patients with oral squamous cell carcinoma.

BACKGROUND: Uridine phosphorylase (UPase) catalyzes the reversible phosphorolysis of uridine to uracil. The expression levels and the enzymatic activity of UPase are reported to be higher in human solid tumors than in adjacent normal tissues. However, to the authors' knowledge the clinical significance of UPase expression as determined by immunohistochemical analysis has not been demonstrated in human malignancies. METHODS: The authors prepared the antibody against UPase, examined the staining of UPase in 72 cases of oral squamous cell carcinoma (SCC) with immunohistochemical analysis using the antibody, and analyzed its relation to clinical and pathologic factors. RESULTS: UPase stained mainly within the invasive edges of tumors and macrophages. UPase-positive staining was observed in 56 of the 72 tumors (77.8%). High staining of UPase (defined as > 50% of cells in a tumor biopsy that are positive for UPase) in primary tumors frequently was associated with the presence of metastasis to lymph nodes (P = 0.007 by the Fischer exact test) and with lower overall survival (P = 0.03 by the log-rank test). CONCLUSIONS: The high rate of UPase staining in biopsies from patients with oral SCC may be a prognostic marker for these individuals.

Adult↗

PubMed2002

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) gene expression in human ovarian carcinoma.

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) that regulates genes involved in response to hypoxia and promotes neo-angiogenesis, is a transcriptional factor for vascular endothelial cell growth factor (VEGF). The aim of this study was to examine the expression of HIF-1 alpha and VEGF gene expressions and their relation to angiogenesis, clinicopathologic variables and survival in the patient with human ovarian carcinoma. We retrospectively analyzed HIF-1 alpha and VEGF gene expression levels using reverse transcriptase polymerase chain reaction (RT-PCR) in 60 ovarian carcinomas. Intratumoral microvessel density (IMD) was assessed by immunostaining endothelial cells, using anti-CD 31 antibody in frozen sections. The relationships between the expression level of these genes, IMD and clinicopathologic variables were evaluated by Student's t-test and chi-square tests. Survival analysis was performed by Kaplan-Meier curves. HIF-1 alpha or VEGF gene expression level was independent of age, clinical stage and histological subtype besides grade of tumor. There was no relationship between HIF-1 alpha or VEGF gene expression level and IMD in all carcinomas (R=0.118 and 0.224, respectively). In addition, a weak association between HIF-1 alpha and VEGF gene expression level was observed (R=0.300, P=0.020). The association between VEGF gene expression and IMD was observed (R=0.501, P=0.016). However, no association between IMD and HIF-1 alpha gene expression was observed. Further, both HIF-1 alpha and VEGF gene expression levels had no effect on survival in the patient with ovarian carcinoma. These results suggest that VEGF upregulated by HIF-1 alpha gene may be involved in angiogenesis of some type of ovarian carcinoma, but the expression levels of both genes have no effect on survival in the patients with ovarian carcinoma.

Adult↗

PubMed2002

Expression of uridine and thymidine phosphorylase genes in human breast carcinoma.

Uridine phosphorylase (UPase) and an angiogenic enzyme, thymidine phosphorylase (dThdPase) are involved in degradation of the pyrimidine nucleosides through phosphorolysis. The expression levels of UPase and dThdPase are higher in human solid tumors including breast carcinomas than in normal tissues. To clarify the correlation between the expression levels of UPase and dThdPase genes and the clinicopathological factors, mRNA levels of these enzymes were examined by RT-PCR in 43 breast carcinomas. UPase gene expression was not correlated with dThdPase gene expression (regression coefficient R = 0.032). Although the expression level of the dThdPase gene was correlated with angiogenesis, detected by immunostaining endothelial cells (R = 0.66), that of UPase gene was not (R = 0.044). These results suggest that UPase does not have a strong angiogenic activity. The UPase gene expression levels in tumors of patients who relapsed were significantly higher than in those from patients who did not (p = 0.039). Although the expression levels of neither UPase or dThdPase were associated with age, pT, pN, pM, estrogen or progesterone receptor positivity, the patients with the higher levels of UPase gene expression had worse survival (p = 0.0038) than those with lower levels. In contrast, the expression of dThdPase gene was not related to relapse or survival of these patients with breast carcinoma. Our findings suggest that the expression level of UPase gene may be an independent prognostic marker in human breast carcinoma.

Adult↗

PubMed2002

Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma.

This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain breast carcinomas. To test this hypothesis, ATP7B expression and protein level were examined in 41 breast carcinomas using RT-PCR and immunohistochemistry. ATP7B gene / protein could be detected in 22.0% (9 / 41) of breast carcinomas and ATP7B gene expression was correlated well with the protein expression. In nine ATP7B-positive tumors, adjacent normal breast tissue was similarly analyzed, revealing that ATP7B is upregulated in breast carcinoma. ATP7B gene expression in poorly differentiated carcinoma was significantly higher than that in well- / moderately differentiated carcinoma (P = 0.012). Furthermore, we found no association between the ATP7B gene / protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that ATP7B gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated breast carcinoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Microdistribution of alpha particles in pathological sections of tissues from thorotrast patients detected by imaging plate autoradiography.

Thorotrast is a colloidal suspension of radioactive (232)ThO(2) that naturally emits alpha particles (90%), beta particles and gamma rays (10%). Thorotrast was used as a radiographic contrast agent in the 1930s-1950s; it caused liver cancer several decades after injection because of its life-long deposition and exposure. Determination of the amount and the distribution of radioactive thorium are essential for assessment of radiation risks. We visualized alpha particles on ordinary archival tissue sections using an imaging plate and a BAS5000 image analyzer. Furthermore, we confirmed that the imaging system is sensitive enough to detect alpha particles and accurate in measuring the total amount of thorium deposited in the organ from a single tissue section. This method revealed that the amount of thorium deposited in tumor tissue is correlated to that in non-tumor tissue. Thorotrast deposition was not associated with DNA damage determined by histochemistry. In combination with histological findings, it is suggested that radioactive thorium always migrates within the deposited organs by macrophages, and that the organs are evenly exposed to alpha particles.

Aged↗

PubMed2002

Overcoming multidrug drug resistance in P-glycoprotein/MDR1-overexpressing cell lines by ecteinascidin 743.

Ecteinascidin 743 (Et-743) is a novel anticancer agent forming covalent guanine adducts at specific sites in the DNA minor groove. Et-743 has a unique mechanism of action because it kills cancer cells by poisoning transcription-coupled nucleotide excision repair. Recent studies suggested a complex relationship between P-glycoprotein (P-gp)/MDR1 and Et-743. On one hand, Et-743 was reported to down-regulate the MDR1 promoter in vitro. On the other hand, P-gp overexpression was hypothesized to contribute to Et-743 resistance in an ovarian cell line. The present study was performed to further investigate the relationship between P-gp/MDR1 and the activity of Et-743. First, we found no P-gp/MDR1 overexpression (mRNA and protein levels) in two independently generated Et-743-resistant human colon carcinoma cell lines (HCT116/ER5 and SW480/ER0.5). Secondly, we found no cross-resistance to Et-743 in two well-characterized P-gp/MDR1-overexpressing cell lines (KB-8-5 and KB-C-2). Third, Et-743 pretreatment enhanced the cytotoxicity and the cellular accumulation of doxorubicin and vincristine in P-gp/MDR1-overexpressing KB-8-5/KB-C-2 cell lines. Fourth, we observed P-gp/MDR1 down-regulation by Et-743 in KB-C-2 cells. These results indicate that Et-743 does not select for the emergence of a P-gp phenotype in all cell lines made resistant to Et-743 and that P-gp overexpression is not sufficient to confer resistance to Et-743. Furthermore, Et-743 is an effective agent in P-gp-overexpressing cells. Et-743 can potentiate the activity of other chemotherapeutic agents by down-regulating P-gp/MDR1, suggesting that the combination of Et-743 and chemotherapeutic agents that are substrates for P-gp/MDR1 may be valuable in the clinic.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Enhanced nucleotide excision repair in cisplatin resistant human KB carcinoma cells.

We previously reported that enhanced active efflux of cisplatin and increased GSH level were observed in KCP-4 cells. In the present study, KCP-4 cells were found to be cross-resistant to ultraviolet (UV) compared with parental KB-3-1 cells. Enhanced nucleotide excision repair (NER) was verified by time-dependent repair of UV-induced DNA damage. In addition, the amount of platinum bound to DNA after exposure to cisplatin decreased in a time-dependent manner in KCP-4 cells and this was reversed by aphidicolin, a DNA polymerase inhibitor. In stationary phase cultures, aphidicolin increased the sensitivity of KCP-4 cells to cisplatin. The expression of xeroderma pigmentosum complementation group F (XPF), an endonuclease involved in NER, was upregulated in KCP-4 cells. In KCP-4 cells the expression of hMSH6, one of the mismatch repair (MMR) factors, was decreased compared to parental KB-3-1 and revertant KCP-4R cells. However, KCP-4 cells were cross-resistant to oxaliplatin, and microsatellite instability was not observed in them. These findings suggest that the enhanced NER activity for DNA damage caused by cisplatin may be involved in cisplatin resistance in KCP-4 cells.

Antineoplastic Agents↗

PubMedDate not supplied

Mutation analysis of copper-transporting P-type adenosine triphosphatase (ATP7B) in human solid carcinomas.

A major obstacle in the treatment of human solid carcinomas is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphatase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. ATP7B is overexpressed in human solid carcinomas such as breast, gastric and oral squamous cell carcinomas. ATP7B expression has an influential effect on some subsets of patients with cisplatin-treated carcinomas. ATP7B mutation is well-known as a cause of Wilson's disease. In addition, the six copper-binding domain and ATP-binding domain of ATP7B are important for the transportation of metals. Therefore, we performed the mutation analysis at the six copper-binding domain and ATP-binding domain of ATP7B. No mutation at the six copper-binding domain and ATP-binding domain was observed in breast, gastric and oral squameous cell carcinomas. These results indicate that the analysis of the ATP7B gene and/or protein will be helpful for the choice of chemotherapy in patients with human solid carcinomas.

Adenosine Triphosphatases↗

PubMedDate not supplied

The proliferative activity of ovarian tumors of low malignant potential differs from that of ovarian carcinoma.

Ovarian tumors of low malignant potential (LMPs) are intermediate between adenomas and ovarian carcinomas (OCs); however, whether an LMP is a precursor of OC or is a unique type of tumor that will not progress to OC is still controversial. To gain better insight into the relationship between LMP and OC, we compared proliferative and apoptotic activity and tumor size in 50 cases of LMP and 27 cases of OC. We employed immunohistochemical staining with Ki-67 and apoptotic labeling was based on the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. The average tumor size observed in mucinous LMP was significantly larger than that in mucinous OC (p = 0.014). In contrast, there was no difference in tumor size between serous OC and serous LMP. The average Ki-67 labeling index (LI) in mucinous OC was significantly higher than that in mucinous LMP (p = 0.028). There was no difference between serous OC and serous LMP in the Ki-67 LI. There was also no difference in apoptotic indeed (AI) between OC and LMP, irrespective of histological subtype. A significant positive relationship between the Ki-67 LI and tumor size was observed in mucinous LMP (R = 0.516, p = 0.0003). Interestingly, the Ki-67 LI was inversely correlated with tumor size in mucinous OC (R = 0.570, p = 0.0317). Significant positive correlations between Ki-67 LI and tumor size were observed in both serous LMP and serous OC (R = 0.707, p = 0.0488, R = 0.789, p = 0.0168, respectively). No association was seen between AI and tumor size in LMP and OC, irrespective of histological subtype. The different associations between proliferative activity and tumor size in the mucinous subtype of LMP and OC suggest that mucinous LMPs may not be precursors of mucinous OCs. In contrast, the similar associations of proliferative activity with tumor size in the serous subtype of LMP and OC suggest that serous LMPs may be precursors of serous OCs.

Adenocarcinoma, Mucinous↗

PubMedDate not supplied

Thymidine phosphorylase expression in gastric carcinoma as a marker for metastasis.

BACKGROUND: Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECCF) and has a function of angiogenesis in vitro and in several types of human carcinoma tissues. We have reported that expression of dThdPase was an independent prognostic factor in 116 gastric carcinomas by immunohistochemical analysis. MATERIALS AND METHODS: In the present study, we updated the analysis of recurrence in 116 patients with gastric carcinomas to find how dThdPase plays an important role in progression of gastric carcinoma. RESULTS: Expression of dThdPase was significantly involved in the progression and metastasis of gastric carcinoma. Further, the proportion of recurrence of the patients with dThdPase-positive gastric carcinoma (23 out of 50, 46.0%) was significantly higher than that with -negative gastric carcinoma (5 out of 66, 7.6%) (p < 0.05). Interestingly, the proportion of hematogenous metastasis (liver, lung) of the patients with dThdPase-positive gastric carcinoma (8 out of 8, 100%) was significantly higher than that with -negative gastric carcinoma (0 out of 8, 0%)) (p < 0.05). The proportion of peritoneal metastasis of the patients with dThdPase-positive gastric carcinoma (10/13, 76.9%) was also significantly higher than that with -negative gastric carcinoma (3 out of 13, 23.1%)) (p < 0.05). CONCLUSION: These findings suggested that dThdPase promotes hematogenous and peritoneal metastases in gastric carcinoma. Inhibition of dThdPase may suppress hematogenous and peritoneal metastases in gastric carcinoma and improve prognosis of patients with gastric carcinoma.

Biomarkers, Tumor↗

PubMedDate not supplied

Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) in human hepatocellular carcinoma.

One of the major obstacles in the treatment of hepatocellular carcinoma (HCC) is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the expression of ATP7B has not previously been addressed in human liver and HCC. Our purpose was to investigate ATP7B expression in human liver and hepatocellular carcinoma and its clinical significance. We retrospectively examined the expression of ATP7B in primary hepatocellular carcinoma. Immunohistochemical analysis of ATP7B was performed using a monoclonal antibody against ATP7B in 19 surgically removed hepatocellular carcinomas. A variable degree of cytoplasmic staining of tumor cells was observed in 21.1% (4/19) of the analyzed carcinomas. ATP7B expression was not observed in normal hepatic cells. Strong expression of ATP7B was observed in all the analyzed bile ducts. These findings suggest that overexpression of ATP7B in hepatocellular carcinoma might be associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Further, ATP7B is expressed in bile duct epithelial cells, where it may mediate copper secretion into bile fluid.

Adenosine Triphosphatases↗

PubMedDate not supplied

Alterations of the K-ras and p53 genes and microsatellite instability in sporadic colorectal carcinomas.

BACKGROUND: The international guidelines for the evaluation of microsatellite instability (MSI) in colorectal cancer were defined in 1997 by the National Cancer Institute (NCI). Here, the relationship between MSI, cancer-associated genes and their clinicopathological variables were revaluated using these guidelines. PATIENTS AND METHODS: Mutations of K-ras at exon 1 and p53 at exons 5, 6, 7 and 8 were analyzed in 43 cases of sporadic colorectal carcinoma. MSI was analyzed using the 5 markers recommended by the NCI reference panel. RESULTS: The proportion of p53 mutations in the MSI-H cases (0 out of 5; 0%) was lower than that of non-MSI-H cases (23 out of 38; 60.5%) (p=0.0117). The proportion of p53 mutations in microsatellite stable (MSS) cases (21 out of 34; 61.8%) was higher than that of non-MSS cases (2 out of 9; 22.2%) (p=0.0366). The proportion of K-ras mutations in MSI-H tumors (1 out of 5; 20.0%) was less frequent than in non-MSI-H tumors (19 out of 38; 50.0%) (p=0.2115). CONCLUSION: p53 mutations in MSI-H tumors were much less common than in non-MSI-H tumors. This result suggested that alterations of the p53 gene are not closely associated with carcinogenesis in MSI-H carcinomas.

Aged↗