Publications (29)66.83 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: Bone marrow (BM)-derived endothelial progenitor cells (EPC) play an important role in neovascularization and tumor growth. It has been reported that docetaxel and paclitaxel inhibit angiogenesis, but the effect of docetaxel and paclitaxel on EPC-induced neovascularization has not been examined. We aimed to clarify the cytotoxic and inhibitory effects of these drugs on EPC. The effects of drugs on growth, tube formation, and migration of EPC were analyzed in vitro using a rat BM-derived EPC cell line (TR-BME). Fluorescence-labeled TR-BME cells were injected into tumor-bearing rats and accumulation at the tumor site was analyzed by fluorescence-activated cell sorting (FACS). In in vitro cytotoxicity assays of these drugs in TR-BME, rat endothelial cell line TR-BBB and rat tumor cell line Walker 256, the IC(50) values for TR-BME were higher than those for TR-BBB or Walker 256. Both drugs inhibited tube formation and migration of TR-BME at lower concentrations than the cytotoxic IC(50). In vivo studies showed that a low dose of both drugs inhibited EPC accumulation at the tumor site in tumor-bearing rats, as determined by FACS, and caused a decrease in microvessel density. Docetaxel and paclitaxel directly inhibited EPC-initiated vasculogenesis at low (non-cytotoxic) concentrations, causing suppression of tumor growth.
- [Show abstract] [Hide abstract] ABSTRACT: We here report on a case of metachronous multicentric carcinomas of the biliary tract treated 3 times with curative surgery over 23 years. A 28-year-old woman underwent cholecystectomy because of papillary carcinoma of the gallbladder. After 17 years, 3 carcinomas developed in the biliary tract: intrahepatic cholangiocarcinoma of the left liver, common bile duct carcinoma, and remnant cystic duct carcinoma. They were successfully removed via left hepatectomy combined with pylorus-preserving pancreatoduodenectomy. Furthermore, another intrahepatic cholangiocarcinoma developed 6 years after the second surgery, which was removed again via partial resection of the posterior segment of the liver. Histological findings of carcinomas represented various grades of cell differentiation. No predisposition toward carcinogenesis was found, since neither pancreaticobiliary maljunction nor primary sclerosing cholangitis was present, and the overexpression of cyclooxygenase-2 was negative in all resected specimens. Close monitoring for recurrence is warranted for early detection of metachronous carcinoma that might be effectively treated with repeated resection.
- [Show abstract] [Hide abstract] ABSTRACT: Local treatment often fails in patients with resectable pancreatic cancer due to the postoperative development of distant metastases, especially liver metastases. We determined the prognostic factors for postoperative liver metastases in pancreatic cancer patients following surgical resection with combined radiotherapy. Sixty-four patients with nonmetastatic, resectable pancreatic cancer were entered into this study. All of these patients had pancreatic resection surgery combined with radiotherapy. The development of postoperative liver metastases was carefully followed, and the survival ratio was evaluated using the Kaplan-Meier method. The prognostic importance of clinicopathological factors and molecular characteristics was analyzed by the Cox proportional hazards model. The correlation study was performed using Fisher's exact test. Tumor size, curability, and histological type of differentiation were statistically significant independent prognostic factors. On multivariate analysis, curability and histological type of differentiation were statistically significant. Only tumor size (> or = 3 cm) was significantly correlated with postoperative liver metastases, as well as cyclooxygenase-2 expression. There were three significant prognostic factors in patients with resectable pancreatic cancer who had local therapy. Patients who have a large tumor require particularly careful follow-up for postoperative liver metastases.
- [Show abstract] [Hide abstract] ABSTRACT: We report the case of a 45-year-old Tokyo man who developed alveolar echinococcosis of the liver, which is an extremely rare disorder in Japan, except for Hokkaido, Japan's northernmost island. The findings of multiple clustered cysts on computed tomography were unlike those of any hepatic tumors we had previously encountered. T2-weighted magnetic resonance imaging revealed the characteristic findings of small cysts with a very high signal intensity. The tumors were successfully removed by a hepatic resection. The patient lives in Tokyo, but has visited Hokkaido many times. The exact route of infection in this patient remains unclear. Sliced raw venison, which he reported eating on every visit to Sapporo in Hokkaido, represented the only potential route of infection we could identify. This meat may have somehow become contaminated with embryonated eggs. Nowadays, even city inhabitants are at risk of developing rare diseases due to the rapid development of transportation systems.
- [Show abstract] [Hide abstract] ABSTRACT: Cyclooxygenase (COX)-2 inhibition results in tumor regression; however, little is known about the mechanism. In the present study, using a Walker256 tumor model and a rat bone marrow-derived endothelial cell line TR-BME-2, we analyzed the effects of a new selective COX-2 inhibitor, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2-(5H)-furanone (DFU), on the production of chemokines and growth factors and on the neovascularization. The oral administration of DFU (5 mg/kg/d) significantly suppressed the tumor growth with decreasing microvessel density in vivo, although it showed no direct inhibition of Walker256 cell proliferation in vitro. It was newly found that the recruitment of systemically injected TR-BME-2 cells into the tumor site was significantly inhibited by DFU treatment. In addition, we found that DFU significantly reduced the production of monocyte chemoattractant protein-1 (MCP-1) both in tumor tissues and in the systemic circulation (P < 0.001 and P < 0.001, respectively). Such reduction was not observed in other chemotactic factors, vascular endothelial growth factor and stromal cell-derived factor-1. The induced chemotaxis of TR-BME-2 by serum of tumor-bearing rats was significantly reduced in DFU-treated rat serum, although DFU showed no direct inhibition for TR-BME-2 cells, either cell growth or chemotaxis. Treatment with neutralizing antibodies to soluble mediators, including MCP-1, significantly suppressed the chemotaxis. Regarding the down-regulation machinery of MCP-1 production in vivo, tumor-associated macrophages seem to play crucial roles, because DFU eliminated MCP-1 production in the activated macrophages remarkably but not in Walker256 tumor cells in vitro. In conclusion, COX-2 inhibitor DFU exerts tumor regression activity in a Walker256 tumor model by suppressing MCP-1 production in tumor tissues and in the circulation.
- [Show abstract] [Hide abstract] ABSTRACT: The effects of the nuclear factor (NF)-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), combined with tumor necrosis factor (TNF)-alpha were evaluated in PK-8 pancreatic cancer cells. NF-kappaB was activated by TNF-alpha; however, the administration of DHMEQ abrogated its transcriptional activity. The addition of DHMEQ to TNF-alpha markedly induced apoptosis in PK-8 cells with down-regulation of anti-apoptotic c-FLIP and survivin. Combined treatment significantly suppressed cell viability in vitro, and the anti-tumor effect of DHMEQ was also significant in vivo. We investigated the apoptosis signaling pathway involved in these cell killing effects. Truncated Bid was produced by activated caspase-8, and the subsequent depolarization of the mitochondrial membrane potential (Delta Psi m) peaked at 6 h. Then, the activity of caspase-3 was up-regulated 8-fold. Z-VAD-fmk (a pan-caspase inhibitor) perfectly inhibited the up-regulation of caspase-3 but failed to reverse the cell viability. The above findings indicated that the growth inhibitory effect of combined treatment largely depended on mitochondria-associated caspase-independent apoptosis. The intracellular behavior of apoptosis-inducing factor (AIF) following depolarization of Delta Psi m suggested that AIF executed such a caspase-independent apoptosis. Interestingly, caspase-dependent apoptosis appeared within 6 h, whereas the caspase-independent apoptosis lagged. Thus, the addition of DHMEQ to TNF-alpha was capable of inducing caspase-independent apoptosis in pancreatic cancer cells. Once caspase-independent apoptosis was induced, the apoptosis demonstrated powerful cytotoxicity. Therefore, DHMEQ in combination with TNF-alpha may be a promising treatment for pancreatic cancer.
- [Show abstract] [Hide abstract] ABSTRACT: Gemcitabine (GEM) concurrent with radiation is clinically not well defined. We herein report four cases of chemo-radiotherapy against locally advanced pancreatic cancer using low-dose GEM concurrent with extra-beam radiation. A total of eight cases entered the study. Three were resected and five were non-resected cases. Intraoperative radiation was carried out in every case using an 8 or 10 centimeter cone with a radiation dose of 25 Gy. Postoperative radiation was 2 Gy per day on weekdays for 5 weeks. Four cases were concurrent with low-dose GEM (40 mg/m2) twice a week, whereas the other four were radiation only. With the use of GEM concurrent with radiation, tumor markers decreased more than 80 percent regardless of the tumor resection. CT scan confirmed a necrotic change and the decrease of the tumor size. In conclusion, low dose GEM concurrent with radiation therapy may be a promising therapeutic choice for the local control of advanced pancreatic cancers.
- [Show abstract] [Hide abstract] ABSTRACT: Patients with gallbadder cancer associated with remarkable lymph node involvement along the para-aortic region are usually excluded from therapeutic plans because of their oppressive outlook. We experienced two patients with Stage IV gallbadder cancer who had undergone intra-aortic infusion chemotherapy and experienced its tumoricidal effects. By keeping the tip of the catheter in the aorta at the Th 9-10 level, we intended to improve the efficiency of drug delivery to both primary lesion and para-aortic metastatic lymph nodes. The anti-cancer drugs employed were gemcitabine (day 3, 9, 1,000 mg/m2/30 min) and low-dose CDDP (day 1-5, day 8-12, 5 mg/30 min) combined with 5-FU (day 1-5, day 8-12, 250 mg/24 h). Day 15-21 was the treatment-free time for recovery from drug toxicities. Since this regimen was well tolerated, the patients could undergo this plan repeatedly. The evidence on CT scans or cholangiography revealed remarkable regression of both primary tumor and metastatic lymph nodes, or resolution of the biliary obstruction. The survival periods from the induction of the treatment were 12 and 14 months, respectively. Thus intra-aortic infusion chemotherapy may be beneficial for the treatment of gallbladder cancer associated with para-aortic lymph node involvement.
- [Show abstract] [Hide abstract] ABSTRACT: We previously designed and synthesized the new nuclear factor kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-kappaB is constitutively activated. The addition of DHMEQ (10 microg/mL) completely inhibited the activated NF-kappaB for at least 8 hours. On the other hand, NF-kappaB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-alpha, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-kappaB activity.
- [Show abstract] [Hide abstract] ABSTRACT: Despite extensive evaluation based on clinical history, biochemical tests, and noninvasive imaging studies, the cause of acute pancreatitis cannot be determined in 10 to 30% of patients, and a diagnosis of idiopathic acute pancreatitis is made. The purpose of this study was to clarify the pancreatographic findings in patients with idiopathic acute pancreatitis. Endoscopic retrograde cholangiopancreatography (ERCP) was performed in 34 patients with idiopathic acute pancreatitis, and the pancreatographic findings were examined. Patency of the accessory pancreatic duct was examined by dye-injection endoscopic retrograde pancreatography (ERP) in 16 of the 34 patients. In 11 patients (32%), the following anatomic abnormalities of the pancreatic or biliary system were demonstrated: complete pancreas divisum (n = 5), incomplete pancreas divisum (n = 2), high confluence of pancreaticobiliary ducts (n = 2), choledochocele (n = 1), and giant periampullary diverticulum (n = 1). Pancreatographic findings were normal in 17 patients. Eleven of these patients were examined by dye-injection ERP, and all were found to have nonpatent accessory pancreatic duct. Anatomic abnormality of the pancreatic or biliary system is one of the major causes of idiopathic acute pancreatitis. Closure of the accessory pancreatic duct may play a role in the development of idiopathic acute pancreatitis in patients with a normal pancreaticobiliary ductal system.
- [Show abstract] [Hide abstract] ABSTRACT: We previously designed and synthesized the new nuclear factor kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquino-micin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-kappaB is constitutively activated. The addition of DHMEQ (10 [mug/mL) completely inhibited the activated NF-kappaB for at least 8 hours. On the other hand, NF-kappaB,B is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and ReIB/ p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-alpha,, the inhibitory effects of DHMEQ were still maintained. I.p.. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-kappaB activity.
- [Show abstract] [Hide abstract] ABSTRACT: A 52-year-old male patient was admitted to our hospital for a further examination of liver tumor. He was positive for hepatitis C virus antibody. CT scanning revealed two hyper vascular tumors at the lateral segment of the liver and another one located at segment 8, an indication of hepatocellular carcinoma (HCC). Ascites were not detected and major serological findings were T-Bil 1.1 mg/dl, Alb 3.5 g/dl, ICG R15 12% and PT 88%. Lateral segmentectomy and a partial resection of the segment 8 were performed at the same time. An insertion of catheter in hepatic artery via gastroduodenal artery was carried out. Dehydropyrimidine dehydrogenase (DPD) activity of the tumor was 157 pmol/min/mg proteins. Recurrence was detected one year after the operation at segments 4 and 8. Arterial infusion chemotherapy using CDDP (10 mg), 5-FU (1,000 mg) and IFN-beta 3MU (continuous infusion for 5 days) was started two months later, and a complete response was achieved. The chemotherapy continued as long as severe adverse effects were not observed. However, two months after the tumor disappearance, the treatment discontinued due to occlusion of the infusion system. Recurrence occurred in two months at the same location where the previous tumor was. In conclusion, these results suggest that arterial chemotherapy using CDDP/5-FU/IFN-beta against HCC may be beneficial.
- [Show abstract] [Hide abstract] ABSTRACT: Cyclooxygenase-2 (COX-2) inhibitors are regarded as potentially important in strategies for cancer treatment. however, the precise mechanisms of these anti-inflammatory drugs as anti-cancer therapy are still unknown. In this study, we examined the effect of DFU both in vitro on MCF-7 cell growth, as well as in vivo on tumor growth produced by MCF-7 cell injection in mice. DFU has growth inhibitory effects on tumor growth in mice compared to the control group. We examined the tumor tissues for apoptosis and angiogenesis by immunostaining. Apoptosis was detected only in the treatment group. DFU treatment also resulted in the inhibition of angiogenesis, as well as decreased COX-2 expression. Results of this study suggest that inhibitory effects of DFU might be COX-2 dependent.
- [Show abstract] [Hide abstract] ABSTRACT: We analyzed 144 patients with pancreatic adenocarcinoma who had received intraoperative radiation therapy (IORT) in combination with external beam radiation therapy (EBRT) within the past 20 years. The patients were divided into 2 groups: group 1 contained 65 patients with locally unresectable tumors who underwent bypass operations and group 2 contained 68 patients with resectable tumors who underwent pancreatic resection. As a pilot study, we performed additional arterial infusion chemotherapy after changing peripancreatic hemodynamics during EBRT in the remaining 11 patients. The 30 patients who received R0 resection had the best survival rates (3-year survival rate of 35.4%), while 3 patients with stage III disease survived more than 5 years. The survival of group 1 patients nearly equaled that of group 2 patients who underwent R1 or R2 resection (median survival, 10.9 vs. 11.1 months, respectively; P = 0.43). The 1-year survival rate for the 11 patients receiving arterial infusion chemotherapy was 45.4%, and 5 patients survived over 1 year without developing hepatic metastasis or regrowth of primary tumors. The survival benefits obtained using this form of radiotherapy are apparently limited. On the other hand, additional arterial infusion chemotherapy employing a new drug delivery system using hemodynamic change does appear promising.
- [Show abstract] [Hide abstract] ABSTRACT: To clarify whether nonmyeloablative allogeneic stem cell transplantation (NST) can produce the graft versus tumor (GVT) effect in patients with pancreatic cancer. A pilot trial of NST was conducted in 5 patients with unresectable pancreatic cancer. Preparative conditioning consisted of administration of 60 mg/kg cyclophosphamide on days 6 and 7 before transplantation, followed by 25 mg fludarabine per square meter of body surface on each of the last 5 days prior to transplantation. Cyclosporine was started 4 days before transplantation. Peripheral blood stem cells from the patients' HLA-identical siblings were transfused into the patients. Complete donor T-cell chimerism in peripheral blood was obtained in 4 patients on day 15 after transplantation. NST resulted in tumor reduction in 2 patients as determined by CT, decreasing levels of tumor markers in 2 patients, pain relief in 2 patients, and a decrease in pleural fluid in 1 patient. Two patients developed acute graft versus host disease (GVHD) of grade II or III and 2 had chronic GVHD involving skin and/or liver. Administration of immunosuppressive drugs for the treatment of GVHD resulted in the elevation of tumor marker levels. These findings are the first to suggest that NST induces a GVT effect on pancreatic cancer.
- [Show abstract] [Hide abstract] ABSTRACT: To test the hypothesis that genetically modified bone marrow-derived endothelial progenitor cells (EPCs) can be effective carriers of therapeutic agents to tumor sites, we utilized our conditionally immortalized endothelial progenitor cell line, TR-BME-2. In the syngenic rat, systemically injected TR-BME-2 cells were immediately distributed to the organs (lung, bone marrow, peripheral blood, liver, spleen). Trapped cells were cleared within 4 days, but selective accumulation in the Walker256 tumor was maintained for over 4 days. The tumor growth was enhanced by administration of TR-BME-2 cells. It is suggested that accumulated TR-BME-2 differentiated to tumor vasculature, increased the tumor blood supply, and thereby increased the tumor volume. We conducted IL-12 gene transfection of TR-BME-2 cells with a virus vector in vitro, and used the resultant IL-12-secreting TR-BME-2 to deliver IL-12, which strongly activates cytotoxic lymphocytes and natural killer cells, to the tumor site in vivo. However, the tumor-progressive character of TR-BME-2 offset the anti-tumor effect of IL-12. Nevertheless, our results suggest that gene-transfected EPCs could be useful as a tumor-specific drug delivery system, especially if the tumor vasculature-promoting effect of EPCs can be blocked.
- [Show abstract] [Hide abstract] ABSTRACT: Radiotherapy employing intraoperative radiation therapy (IORT) in combination with postoperative external beam radiation therapy (EBRT) is an effective treatment for unresectable pancreatic cancer. To achieve an even greater therapeutic outcome, 13 patients with unresectable pancreatic cancer were treated by IORT in combination with EBRT plus locally intensive arterial infusion chemotherapy. In order to increase drug delivery to the primary tumor, the splenic and major pancreatic arteries, except for the gastroduodenal artery (GDA), were embolized by radiological intervention prior to the arterial infusion chemotherapy, and the administration of gemcitabine, CDDP, and 5-FU to the primary tumors via GDA was followed during EBRT. The values of serum tumor markers were decreased in all patients, and tumor regression was detected on CT scans in 6 patients. The evaluation of survival benefit of this treatment modality is ongoing, but it did not prolong the survival time of patients with second stage lymph node metastases. One of the advantages of this method was able to perform also in charge of hepatic arterial infusion chemotherapy concurrently, but we experienced liver abscess in 2 patients.
- [Show abstract] [Hide abstract] ABSTRACT: Peripheral stem cells released from bone marrow (BM) are known to be incorporated into foci of neovascularization and to contribute to solid tumor development. In the present rat Walker256 tumor model, BM suppression induced by total body irradiation resulted in poor growth of the tumor with apparently poor vascularization, and BM transplantation restored tumor growth. Endothelial progenitor cells are considered to be crucial for vasculogenesis, but they are not yet well defined, and methodology for their purification has not been established. As a model to examine the significance of endothelial progenitor cells in tumor-specific vasculogenesis, we utilized an immortalized rat BM-derived endothelial cell line named TR-BME-2. Fluorescence-labeled TR-BME-2 cells injected systemically into rats were accumulated at the tumor site 4 days later. Another rat BM-derived cell line named C2-11, which does not have an endothelial profile, did not show tumor-specific accumulation. The tumor volume in rats treated with TR-BME-2 was significantly larger than that in rats treated with C2-11. Thus, our results suggest the importance of neovascularization by bone marrow-derived endothelial cells for the promotion of tumor growth.
Edo, Tokyo, Japan
- Department of Applied Chemistry