Biomedical subjects

T Aikou

Publications and source records attributed to T Aikou.

At least 109 records · Page 6Linked to original sources

PubMed1998

Prevention of hypoxia-induced apoptosis by the angiogenic factor thymidine phosphorylase.

The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is expressed at higher levels in a wide variety of solid tumors compared to adjacent normal tissues. Patients with PD-ECGF/TP-positive colon and esophageal tumors have a poorer prognosis than those with negative tumors. The expression of PD-ECGF/TP is a prognostic factor independent of microvessel density suggesting that TP has effects on tumor progression independent of its angiogenic activity. Evidence that hypoxia and apoptosis affect tumor growth prompted us to determine whether increased expression of PD-ECGF/TP prevents apoptosis induced by hypoxia. KB/TP cells transfected with a PD-ECGF/TP cDNA were resistant to hypoxia-induced apoptosis. Among the degradation products of thymidine produced by PD-ECGF/TP, 2-deoxy-D-ribose and thymine partially prevented hypoxia-induced apoptosis. The ability of 1 microM 2-deoxy-D-ribose in combination with the same concentration of thymine to prevent hypoxia-induced apoptosis was similar to that of the overexpressed TP in KB cells. A concentration of 1 microM 2-deoxy-L-ribose abrogated the effects of these degradation products of thymidine. These findings suggested that TP can confer resistance to apoptosis induced by hypoxia and the degradation products of thymidine are involved in this resistance. Expression of PD-ECGF/TP may play an important role in the progression of solid tumors, and inhibitors of TP and analogs of the degradation products of thymidine may suppress the growth of tumors by promoting apoptosis.

Angiogenesis Inducing Agents↗

PubMed1998

Selectins induced by interleukin-1beta on the human liver endothelial cells act as ligands for sialyl Lewis X-expressing human colon cancer cell metastasis.

We have previously reported that colon cancer cells metastasized to the liver expressed an increased amount of sialyl Lewis X (SLeX) antigen compared to their corresponding primary lesions. It is now well known that SLeX antigen and sialyl Lewis A (SLeA) antigen are ligands for the selectins expressed on the endothelial cells. Therefore, it is assumed that SLeX-rich colon cancer cells could be easily adhered to the endothelial cells that express selectins. In this report we have tried to induce selectin expression on the human liver sinusoidal endothelial cells and have examined the adhesion of SLeX-high or -low expressing colon cancer cells to the interleukin-1beta (IL-1beta)-treated liver specimens using Stamper-Woodruff assay. These human colon cancer cells are termed KM12HX or KM12LX cells, respectively. A significantly increased number of KM12HX cells adhered to the IL-1beta-treated liver specimens compared to KM12LX cells. The adhesion of KM12HX cells was inhibited by the pretreatment of tumor cells with anti-SLeX antibody or by the pretreatment of liver specimens with anti-selectin antibodies. Selectin expression on the liver sinusoidal endothelial cells and endothelial cells of blood vessels after IL-1beta treatment was confirmed by immunohistochemically using anti-selectin monoclonal antibodies (MAbs). These findings strongly suggest that SLeX-expressing cancer cells could adhere to the sinusoidal endothelial cells via an SLeX-selectin interaction system and this could be a first step for colon cancer cells that metastasize to the liver. The mechanism by which these selectins can be induced in vivo is the next problem to be considered.

Cells, Cultured↗

PubMed1998

In vitro determination of basement membrane invasion predicts liver metastases in human gastrointestinal carcinoma.

We described previously (H. Imamura, et al., Cancer Res., 54: 3620-3624, 1994) a quantitative and reproducible 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for tumor cell invasiveness that uses a water-repellent, paraffin-treated Chemotaxicell chamber to produce a uniform Matrigel layer. In the present experiments, we studied 71 human gastrointestinal carcinomas, including 53 maintained as xenografts in nude mice and 18 fresh surgical specimens. We found a correlation between metastatic behavior and the percent invasion (PI) calculated from the MTT assay. Tumors producing liver metastases had a significantly higher PI than did tumors without liver metastases (P < 0.01), and seven of nine fresh tumors with a PI greater than 1.0 showed liver metastases within 2 years. No significant correlations were noted between the PI and clinicopathological factors. In the tumor xenografts, type IV collagenase activity was significantly higher in tumors with clinically evident liver metastases than in those without liver metastases (P < 0.05). Colorectal carcinomas with liver metastases and a high PI showed higher expression of matrix metalloproteinase 9 than matrix metalloproteinase 2 as assessed by gelatin zymography. Thus, the invasion-MTT assay is clinically useful for predicting liver metastases. Type IV collagenase plays an important role in the development of liver metastases from human gastrointestinal carcinoma.

Animals↗

PubMed1998

Increased sensitivity to vincristine of MDR cells by the leukotriene D4 receptor antagonist, ONO-1078.

The leukotriene D4 (LTD4) receptor antagonist, 4-oxo-8-[p-(4-phenylbutyloxy)benzoylamino]-2-(tetrazol-5-yl) -4H-1-benzopyran hemihydrate (ONO-1078) is used for the treatment of allergic asthma and other immediate hypersensitivity diseases. We examined the effect of ONO-1078 on the sensitivity to vincristine (VCR) of MRP overexpressing multidrug-resistant CV60 and its parental drug-sensitive KB-3-1 cell lines. The sensitivity to VCR of KB-3-1 and CV60 cells was increased 13- and 15-fold, respectively, by ONO-1078 at the maximum non-toxic concentration (100 microM). The VCR sensitivity of multidrug-resistant KB-C2 cells that overexpressed P-gp was increased 2.6-fold by ONO-1078. The accumulation of VCR in KB-3-1, CV60 and KB-C2 cells was significantly increased by ONO-1078. The efflux of VCR from KB-3-1 cells was not inhibited, but that from CV60 cells was enhanced compared with that from KB-3-1 cells and was partially inhibited by ONO-1078. ONO-1078 competitively inhibited the ATP-dependent [3H]LTC4 uptake in membrane vesicles isolated from CV60 cells. These findings suggest that ONO-1078 inhibits the transporting activity of MRP and that ONO-1078 increases the sensitivity to VCR of KB-3-1 cells by increasing the VCR uptake in the cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Reversal of MRP-mediated vincristine resistance in KB cells by buthionine sulfoximine in combination with PAK-104P.

The mechanism of multidrug resistance protein (MRP)-mediated multidrug resistance (MDR) is still unclear. MRP reportedly transports some GSH conjugates. Recently, we demonstrated that a pyridine analog, 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl 5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4 -(3-nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P), that reversed P-glycoprotein (P-gp)-mediated MDR directly interacted with MRP and completely reversed the vincristine (VCR) resistance in MRP-mediated MDR C-A120 cells. We investigated the reversing effect of PAK-104P in C-A120 cells in combination with buthionine sulfoximine (BSO), another MDR-reversing agent with a different reversing mechanism. In immunoblots, MRP was overexpressed in C-A120 cells. The level of ATP-dependent [3H]VCR uptake was high in membrane vesicles from KB-C2 cells, but low in those from C-A120 and parental KB-3-1 cells. The sensitivity to VCR of C-A120 cells, but not of KB-C2 cells, was considerably increased by 100 microM BSO. VCR accumulation in C-A120 cells, but not in KB-C2 cells, was also enhanced by BSO. BSO did not inhibit ATP-dependent [3H]LTC4 uptake in C-A120 vesicles. The combination of BSO with PAK-104P at their low concentrations resulted in complete reversal of VCR resistance in C-A120 cells. These findings suggested that BSO might not directly interact with MRP and reversed resistance in MRP-mediated MDR cells by reducing the intracellular glutathione (GSH) level that was needed for the transport of drugs by MRP and suggested a role for the combination of drug resistance-modulating agents with different reversing mechanisms in the reversal of MRP-mediated MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Design and testing of a new cisplatin form using a base material by combining poly-D,L-lactic acid and polyethylene glycol acid against peritoneal metastasis.

Microspheres containing cisplatin (CDDP) embedded in poly-d,l-lactic acid (PLA) and polyethylene glycol acid (CDDP-PPMS) were developed to improve treatment of malignant effusions. In vitro studies demonstrated that CDDP was released continuously for more than 4 weeks from CDDP-PPMS without initial burst. CDDP-PPMS was compared with CDDP aqueous solution (CDDP-SOL) by i.p. administration in rats for 1) tissue distribution, 2) toxicity and 3) therapeutic effects against Yoshida sarcoma. We found that the CDDP concentration in the omentum was maintained at a higher level than in the CDDP-SOL group, while the particles of CDDP-PPMS were observed in the stomata of the omentum by electron microscopy. Concentrations of CDDP in the lung, liver, kidney and blood were lower in the CDDP-PPMS group than in the CDDP-SOL group. All rats given CDDP-PPMS containing < or = 28 mg/kg were alive, whereas in the CDDP-SOL group, all rats given > or = 16 mg/kg died from side effects. The LD50 of CDDP-PPMS and CDDP-SOL were 32.8 and 14.8 mg/kg, respectively. The survival of rats with peritoneal metastasis was better in the CDDP-PPMS group than in the CDDP-SOL group.

Animals↗

PubMed1998

A subcloned human esophageal squamous cell carcinoma cell line with low thrombomodulin expression showed increased invasiveness compared with a high thrombomodulin-expressing clone--thrombomodulin as a possible candidate for an adhesion molecule of squamous cell carcinoma.

Thrombomodulin (TM) is an endothelial cell surface glycoprotein which converts thrombin from a procoagulant protease to an anticoagulant. We have previously reported that TM is a useful marker for immunohistochemical diagnosis of angiogenic tumors and also have reported that TM is expressed on squamous cell carcinoma (SCC) of the human esophagus. In addition, the expression of TM is significantly decreased in metastatic foci in lymph nodes compared with that in primary lesions. In order to reveal the biological significance of TM in SCC, we subcloned and established two different cell lines, i.e. TM-high-expressing (TE3HTM) cells and TM-low-expressing (TE3LTM) cells, from a human SCC cell line, TE3, using fluorescence-activated cell sorter (FACS) and examined the biological characteristics of these variant cell lines. These tumor cells revealed very similar morphological figures in ordinary cultured conditions and showed almost equal growth rates under various cultured conditions. By the invasion assay of these tumor cells using matrigel, we found that TE3LTM cells showed significantly increased invasive ability compared with that of TE3HTM cells. Characteristic intercellular localization of TM and a different manner of invasiveness between TE3LTM cells and TE3HTM cells suggest that TM may act as a cell-to-cell interaction molecule.

Carcinoma, Squamous Cell↗

PubMed1998

The expression of multidrug resistance protein in human gastrointestinal tract carcinomas.

BACKGROUND: Multidrug resistance protein (MRP) is a membrane phosphoglycoprotein with an Mr of 190,000 that is involved in the non-P-glycoprotein mediated multidrug resistance of human tumor cells. The aim of this study was to determine the clinicopathologic relevance of MRP expression in human gastrointestinal tract carcinomas. METHODS: The authors prepared a rabbit antiserum against MRP that does not cross-react with P-glycoprotein and retrospectively examined the expression of MRP in 86 squamous cell carcinomas of the esophagus, 103 adenocarcinomas of the stomach, and 139 colorectal adenocarcinomas by immunohistochemistry. None of the patients in this study had received prior chemotherapy. RESULTS: The proportion of MRP positive samples in the squamous cell carcinomas of the esophagus (62.8%, 54 of 86) was significantly higher than that in the adenocarcinomas of the stomach (34.1%, 35 of 103) and the colorectal adenocarcinomas (40.3%, 56 of 139) (P <0.01). The proportion of MRP positivity in the well-differentiated carcinomas was significantly higher than that in moderately or poorly differentiated carcinomas. MRP expression was independent of gender, lymph node metastasis, and tumor progression. CONCLUSIONS: These data indicate that the expression of MRP is correlated with the differentiation of carcinoma cells in the gastrointestinal tract and may be involved in the intrinsic drug resistance of well-differentiated squamous cell carcinoma of the esophagus.

ATP-Binding Cassette Transporters↗

PubMed1998

Postoperative management following massive hepatectomy in a patient with Dubin-Johnson syndrome: report of a case.

We report herein the case of a 46-year-old man with Dubin-Johnson syndrome (DJS) who was referred to our hospital to undergo a right hepatic lobectomy for hepatocellular carcinoma. His complicated postoperative conjugated hyperbilirubinemia was successfully treated by hemopurification based on the increased level of serum hepatocyte growth factor (HGF). It is considered that hemopurification based on the early postoperative HGF levels has beneficial effects for patients with DJS; however, the specific role of hemopurification in the conjugated hyperbilirubinemia that develops postoperatively in these patients has not been determined.

Carcinoma, Hepatocellular↗

PubMed1998

Carcinomatous infiltration into the submucosa as a predictor of lymph node involvement in early gastric cancer.

The clinicopathologic features of 114 patients with resectable early gastric cancer (EGC) invading the submucosa were examined retrospectively with respect to lymph node involvement and the possibility of performing a minimally invasive operation. Patients were divided into node-positive (n = 25) and node-negative (n = 81) groups. Among several pathologic factors, the diameter of the tumor and lymphatic involvement were significantly correlated with nodal involvement. Within the submucosal layer the depth of invasion and the horizontal cancerous expansion also correlated with lymph node disease (p < 0.05). The size of the tumor did not correlate with the length of submucosal infiltration (r = 0.12, p = 0.1). Patients with both slight invasion into the submucosa and less than 5 mm of horizontal expansion were often negative for lymph node involvement and thus may benefit from local surgery as an alternative to gastrectomy.

Adenocarcinoma↗

PubMed1998

Diffusely infiltrative squamous cell carcinoma of the esophagus.

This study was designed to clarify the clinical and pathologic features of diffusely infiltrative squamous cell carcinoma of the esophagus. Diffusely infiltrative squamous cell carcinomas were classified grossly into two types, namely, scirrhous carcinoma and nonscirrhous carcinoma. There were seven patients with the former type and three with the latter type. Scirrhous-type carcinoma was associated with a prominently thickened esophageal wall with strictures, whereas nonscirrhous-type carcinoma demonstrated thickening of the esophageal wall without strictures. Microscopically, all patients had lymph node metastases and lymphatic invasion. Blood vessel invasion was found in seven patients and extranodal invasion was found in seven. The prognosis of patients with both types of carcinoma was extremely poor. Only two patients who underwent curative surgery as well as chemoradiotherapy survived for more than 1 year. Therefore, further morphological studies on the early stages of diffusely infiltrating esophageal carcinoma should be performed. New treatment strategies such as intensive preoperative chemoradiotherapy based on sensitivity tests in individual patients will be required for treating the advanced stages of this disease.

Aged↗

PubMed1998

The expression of cadherin-catenin complex in association with the clinicopathologic features of early gastric cancer.

Although impaired expression of E-cadherin (E-cad) is frequently observed in tumors with aggressive histopathologic characteristics, the correlation between alpha-catenin (alpha-cat) expression and the clinicopathologic features of early gastric cancer have not been fully examined. In this study, we evaluated the expression of E-cad and alpha-cat by early gastric carcinomas, and examined the relationships between this expression and various clinicopathologic characteristics. A total of 69 specimens obtained from surgery were studied by immunohistochemistry. Reduced expression of E-cad and alpha-cat were found in 53.6% and 65.2% of the tumors, respectively, and a significant correlation was observed between the decreased expression of E-cad or alpha-cat and tumor histology, the quantity of stroma, and the infiltration pattern of the tumor. The reduced expression of alpha-cat correlated more strongly with these features than E-cadherin expression. Furthermore, alpha-cat expression was also related to the lymph node metastasis of tumors. The expression of E-cad or alpha-cat in the primary tumor was consistent with the expression of tumor cells that invaded the lymphatic vessels, but discordant with staining in the metastasized lymph nodes. In some cases, as the tumor invaded deeper, the expression of E-cad or alpha-cat changed from preserved to reduced. Our observations suggest that the reduced expression of E-cad or alpha-cat may be involved in the initial steps leading to the invasion and metastasis of early gastric cancer.

Adult↗

PubMed1998

An activated state of blood coagulation and fibrinolysis in patients with abdominal aortic aneurysm.

BACKGROUND: Relationships between blood coagulation and the fibrinolysis system and morphology of aneurysms in patients with abdominal aortic aneurysm (AAA) are unknown. METHODS: Preoperative and postoperative evaluations of hemostatic factors such as thrombin-antithrombin III complex (TAT), D-dimer, fibrinogen/fibrin degradation products (FDP), and platelet count were performed in 36 patients with atherosclerotic AAA. As control subjects, 25 age- and sex-matched healthy volunteers were analyzed for these hemostatic factors. In all patients, morphological evaluation of AAA included the largest diameter, tortuosity, and the thickness of intraluminal thrombus to be compared with preoperative levels of hemostatic factors such as alpha-2 plasmin inhibitor-plasmin complex (PIC), thrombomodulin (TM), von Willebrand factor (vWF), tissue factor (TF), and free form of tissue factor pathway inhibitor (F-TFPI). RESULTS: The preoperative values of TAT, D-dimer, and FDP were significantly higher in AAA patients than in controls. Of all patients, 23 (64%) or 22 (58%) had TAT or D-dimer values greater than 8.2 ng/mL or 3.4 microg/mL (mean + 2SD of controls), respectively. The postoperative values of these hemostatic factors significantly improved, but were not normalized. The largest diameter of AAA correlated with the preoperative levels of TAT (r = 0.566, P = 0.001), D-dimer (r = 0.644, P = 0.0001), FDP (r = 0.561, P = 0.0009), PIC (r = 0.413, P = 0.0146), and F-TFPI (r = 0.408, P = 0.0158). We have also found that tortuosity of AAA has relation not only to the preoperative levels of fibrinolytic factors but also to the plasma F-TFPI antigen levels. On the other hand, the preoperative levels of a marker of endothelial damage, such as TM or vWF, and TF did not correlate with those of F-TFPI in all patients. The maximum thickness of thrombus in AAA significantly correlated not only with the preoperative levels of TAT, D-dimer, FDP, and PIC, but also with AAA size. CONCLUSIONS: We have found evidence that an activated state of both blood coagulation and fibrinolysis in AAA patients is associated with the morphological characteristics of aneurysms.

Aged↗

PubMed1998

Comparison of relapse and long-term survival between pylorus-preserving and Whipple pancreaticoduodenectomy in periampullary cancer.

BACKGROUND: Whether long-term survival and type of recurrence in periampullary cancer are influenced by the type of surgical procedure or not is still obscure. The purpose of this review was to analyze the results at a single institution. METHODS: Between 1982 and 1996, 113 consecutive patients with either distal bile duct or ampullary cancers underwent either pylorus-preserving pancreaticoduodenectomy (PPPD) or the Whipple procedure. The median follow-up was 30 months (range 12 to 150). Patient records were reviewed to determine type of recurrence and survival. RESULTS: In distal bile duct or ampullary cancers, comparison of actuarial survival curves between PPPD and the Whipple operation revealed no significant differences. Even in node-positive patients, the 5-year survival rates did not differ significantly between those undergoing PPPD or the Whipple operation. Tumor recurrence was not correlated with the operative method, although among types of tumor recurrence, the rate of blood-borne metastasis was higher in distal bile duct or ampullary cancers. CONCLUSIONS: PPPD is an acceptable alternative to the Whipple procedure in the treatment of periampullary cancer. Long-term survival and type of recurrence were not influenced by these types of surgical procedures.

Adult↗

PubMed1998

Truncated midkine as a marker of diagnosis and detection of nodal metastases in gastrointestinal carcinomas.

Midkine (MK) is a growth factor identified as a product of a retinoic acid-responsive gene. A truncated form of MK mRNA, which lacks a sequence encoding the N-terminally located domain, was recently found in cancer cells. We investigated the expression of the truncated MK mRNA in specimens of 47 surgically removed human gastrointestinal organs using polymerase chain reaction. Truncated MK was not detected in all of the 46 corresponding non-cancerous regions. On the other hand, this short MK mRNA was expressed in the primary tumours in 12 of 16 gastric cancers, 8 of 13 colorectal carcinomas, five of nine hepatocellular carcinomas, two of two oesophageal carcinomas and one ampullary duodenal cancer. In addition, truncated MK was detectable in all of the 14 lymph node metastases but in none of three metastatic sites in the liver, suggesting that truncated MK mRNA could become a good marker of nodal metastases in gastrointestinal tract.

Biomarkers, Tumor↗

PubMed1998

Massive hemorrhage after biopsy of an esophageal polyp.

Esophageal vascular malformations are very rare. Herein, we describe a rare polyp formed by an abnormally large vessel that bled profusely after biopsy. Despite endoscopic procedures, the patient continued to bleed and underwent emergency surgery. Histopathological examination revealed an abnormally large blood vessel with a thick wall in the upper part of the lamina propria mucosae and covered by squamous cell epithelium. The elevated lesion, which was endoscopically diagnosed a small polyp, was in fact an abnormally large artery covered by squamous cell epithelium. Massive bleeding after biopsy of an esophageal polyp is apparently so rare that it has not, as yet, been described.

Aged↗

PubMed1998

Detection of lymph node metastasis using desmoglein 1 expression in superficial esophageal cancer in relation to the endoscopic mucosal resection.

Endoscopic mucosal resection (EMR) has recently been standardized for mucosal cancer of the esophagus. It may be hypothesized that EMR may be considered to be curative for superficial esophageal cancer (SEC), if the possibility of lymph node metastasis can be excluded beforehand. Ninety patients with p-T1 tumours who underwent esophagectomy were studied. Their primary lesions were stained with anti-Desmoglein 1 antigens using the ABC method. The p-T1 tumors were subdivided into three categories: carcinoma limited to the lamina propria mucosae (19 patients, SEC1), carcinoma invading the lamina muscularis mucosae or with invasion just into the submucosa (27 patients, SEC2), and carcinoma definitely invading the submucosa (44 patients, SEC3). Lymph node metastasis was not observed in the SEC1 patients but was observed in 19% of the SEC2 patients and 41% of the SEC3 patients. None of the SEC1 or SEC2 patients had lymph node metastasis when preserved Desmoglein 1 expression was obtained. The EMR appears to be appropriate therapy for SEC1. Our findings indicate that, for SEC2, preserved expression of Desmoglein 1 may be a helpful aid to exclude the possibility of lymph node metastases. Transthoracic esophagectomy with lymphadenectomy should be selected in the SEC3 patients.

Aged↗

PubMed1998

The expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor is correlated to angiogenesis in breast cancer.

It has been shown that human thymidine phosphorylase (TP) is identical to platelet-derived endothelial cell growth factor and has angiogenic activity. In the present study, the expression of TP was examined in 139 mammary carcinomas and 35 benign mammary disorders using biochemical and immunohistochemical methods. Moreover, in order to evaluate the significance of TP expression in mammary carcinomas, the relationship between vascular density and various clinicopathological factors, including age and menopausal status of patients with a mammary carcinoma, were compared with the size, nodal status, expression of estrogen receptor (ER), progesterone receptor (PgR), c-erbB-2, p53 and TP of a mammary carcinoma. Thymidine phosphorylase expression increased in both the nuclei and cytoplasm of mammary carcinoma cells in comparison to mammary benign disorder cells. The number of microvessels in mammary carcinomas was generally correlated to the number of tumor cells with TP expression in cytoplasm. The number of cells with TP expression in cytoplasm was significantly large in tumors that measured 3-4 cm in diameter, compared with tumors measuring 1-2 and 5-6 cm in diameter. In mammary tumors of 1-4 cm diameter, TP expression and vessel density were significantly high in tumors negative for ER or positive for c-erbB2 and in tumors positive for TP or c-erbB2, respectively; whereas tumors of 5-6 cm in diameter were not modified by any clinicopathological factors. The results indicated that TP plays an important angiogenetic role in mammary carcinomas, especially tumors with a certain progression.

Adult↗