Background/Aim: We investigated the antiproliferative effect of quercetin on liver cancer cell lines. Materials and Methods: Thirteen liver cancer cell lines were cultured followed by treatment with varying concentrations of quercetin (0-100 μM) or quercetin and 5-FU, and the cell viability was analysed by the MTT assay. Flow cytometry was also used to examine cell cycle progression after treatment with quercetin. Results: The addition of quercetin resulted in a dose-and time-dependent suppression of cell proliferation. In some cell lines, treatment with quercetin and 5-FU caused an additional or synergistic effect. Most cell lines displayed cell cycle arrest at different phases of the cell cycle. Conclusion: Quercetin inhibits the proliferation of liver cancer cells via induction of apoptosis and cell cycle arrest.Hepatocellular carcinoma (HCC) is the most frequent primary cancer, and an important medical problem (1). Many HCC patients have a history of chronic hepatitis or liver cirrhosis caused by Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection (2-4). Treatments for poor liver function associated with hepatitis are limited and outcomes are poor. Even with the most successful treatments, the 5year recurrence rate of HCC is very high (1). Treating and preventing recurrence is critical for improving survival rates.Quercetin is a type of flavonoid contained in many plants, and possesses antioxidant, anti-inflammatory, and immuno-logical capabilities (5). Quercetin can suppress cell proliferation and induce apoptosis in human cancers, including breast, lung, oral, and prostate; however, there is no report on its effect on liver cancer (6-9). In the current study, we examined the antitumor effects of quercetin on 13 HCC cell lines in vitro. Materials and MethodsCell lines and cell culture. This study utilized 11 HCC cell lines (KIM-1, KYN-1, KYN-2, KYN-3, HAK-1A, HAK-1B, HAK-2, HAK-3, HAK-4, HAK-5, and HAK-6), and 2 human combined hepatocellular and cholangiocarcinoma (CHC) cell lines (KMCH-1 and KMCH-2). The cell lines were originally established in the Department of Pathology, Kurume University Faculty of Medicine, and each of them retains the morphological and functional features of the original tumor as previously described (10-18). Each cell line was grown in Dulbecco's modified Eagle medium (Nissui Seiyaku, Co., Japan) supplemented with 2.5% heat-inactivated (56˚C, 30 min) fetal bovine serum (Bioserum, Victoria, Australia), 100 U/ml penicillin, 100 μg/ml streptomycin (GIBCO BRL/Life Technologies, Inc., Gaithersburg, MD, USA) and 12 mmol/l sodium bicarbonate, in a 5% CO 2 humidified atmosphere at 37˚C. Effects of quercetin on the proliferation of hepatocellular carcinoma and combined hepatocellular and cholangiocarcinoma cell lines in vitro.The effects of quercetin with and without 5-FU on proliferation were examined using 3-(4,5-dimethylthiazol-2yl-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay kit (Chemicon, Temecula, CA, USA) as previously described (10). Quercetin was obtained from Sigma Chem...

The efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5'-DFUR may not be as great for patients with a tumor positive for MMP-9 having a greater risk to postoperative recurrence.

Aims: 5-Fluorouracil (5-FU) is one of the most widely used anticancer drugs; however, the activity of 5-FU is determined by the presence of several enzymes that limit its activation or degradation, and these include dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), thymidine kinase (TK), thymidine phosphorylase (TP) and deoxyuridine triphosphatase (dUTPase). The aim of this study was to compare the expression levels of these enzymes between the primary colorectal cancer of patients with and without distant metastases. Furthermore, there was a comparison of these expression levels between the primary tumour and the corresponding metastasis. Methods: Of 55 patients with colorectal cancer, 20 had no metastasis and the other 35 had distant metastasis. A strong expression was classified as positive, while weak to moderate or no expression was negative by immunohistochemistry. Results: Of the six 5-FU-related enzymes, the numbers of patients with expression of dUTPase (54% versus 15%; p = 0.005), TK (26% versus 0%; p = 0.019) and DPD (17% versus 45%; p = 0.033) were significantly different in those with primary tumours with metastasis compared with those with non-metastasis, respectively. The altered expression of OPRT (34.3%), TS (40.0%) and dUTPase (42.9%) was significantly greater from primary to metastasis among the 35 patients with metastasis. By contrast, the expression of OPRT, TS and dUTPase was decreased in 6, 5 and 7 patients, respectively, in metastatic sites. Conclusions: From this comparative study of the six 5-FU-related enzymes in colorectal cancer, the expression of dUTPase was most significantly different between primary tumours and their corresponding metastatic tumour. It is suggested that dUTPase may be a predictive biomarker for the metastatic potential of colorectal cancer.5-Fluorouracil (5-FU) is one of the most widely used anticancer drugs for the treatment of cancers of the colon, breast, skin, head and neck, stomach and liver.

We have investigated the antitumor effects of synthetic MMP inhibitor MMI270 against postoperative lung metastasis from colon cancer in nude rat. The KM12SM human colon cancer cells were injected into the cecal wall, and at 5 weeks after the injection, the cecum was removed including the tumor. Then, 30 mg/kg of MMI270 was administered perorally twice per day for 2 or 4 weeks, either immediately after removal or after week 2 after the removal. At week 7 after the removal, lung metastasis was significantly inhibited by the early administration of MMI270 immediately after the tumor removal but not by the late administration. The survival rates were significantly higher in the rats treated by early administration of MMI270 compared to the survival rate in untreated rats. Moreover, no lung metastasis was detected in some rats with 24-weeks' survival treated by early administration. Lower microvessel density, lower PCNA Index and higher Apoptotic Index in the lung metastases of the rats treated with MMI270 were found compared to those in untreated rats. A beneficial effect of by early administration of MMI270 against postoperative lung metastases may be expected through inhibiting neovascularization of metastases in nude rat. ' 2005 Wiley-Liss, Inc.Key words: preclinical lung metastases model; angiogenesis; apoptosis; postoperative adjuvant therapy Colorectal cancer remains one of the major causes of cancer death worldwide. The mainstay of treatment for colorectal cancer with curative intent is surgical resection. However, recurrences to the liver or lung may occur in some patients even after a potentially curative operation. 1 For instance, the overall 5-year-survival rate for stage III cancer is approximately 60 % 2 due to postoperative recurrences even if the patients receive adjuvant chemotherapy. It is thought that the development of distant metastases depends on the spread of cancer cells from the primary tumor and that micrometastases already established prior to primary tumor resection appear as recurrent tumors after the operation. Therefore, to improve the postoperative prognosis of patients with colorectal cancer, effective adjuvant therapies against the micrometastases such as chemotherapy and immunotherapy should be considered. Since the 1990s, chemotherapy using 5-fluorouracil and leucovorin (5-FU/LV) has become standard treatment for stage III colon cancer after successful surgery. 3,4 However, this chemotherapy is still insufficient for patients at a high risk to recurrence who have biologically aggressive tumors, and the need to improve the outcome in such patients has increased the interest in developing more intensive or more targeted therapeutic strategies.It has been shown that solid tumor growth beyond a certain size requires neovascularization to supply the tumor with oxygen and nutrients. 5 In other words, without neovascularization, micrometastasis cannot grow. Therefore, it has been suggested that antiangiogenic therapy is effective against various solid tumors by inhibiting neovascularizat...

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IntroductionLaparoscopic surgery is a minimally invasive approach with good treatment outcomes and is currently the standard surgery for colorectal cancer in Japan. Mesenteric closure is considered unnecessary in laparoscopic colorectal surgery because it can damage the bowel and blood vessels. However, an internal hernia may develop if the mesentery is not repaired.Case presentationWe report a case of internal hernia in a 61-year-old male of Japanese ethnicity. The patient had advanced sigmoid colon cancer, early-stage transverse colon cancer, and multiple adenomatous polyposis, and underwent laparoscopically-assisted subtotal colectomy. Bowel obstruction developed six days postoperatively and did not improve with conservative treatment. Abdominal computed tomography detected an internal hernia, prompting emergency surgery in which the ileum protruding into the mesenteric defect and an anastomotic stricture were detected. Reanastomosis, mesentery closure, and ileostomy were performed after hernia repair.ConclusionIn this case, open surgery was necessary due to bowel obstruction after laparoscopic colectomy. This outcome indicated that mesenteric closure should have been performed. Thus, the benefits of mesenteric closure require assessment in future cases.

Abstract. The aim of this study was to determine any correlation between the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines and the vascular endothelial growth factor (VEGF) expression in primary colorectal cancer tissues. The data were reviewed retrospectively on 342 patients with colorectal cancer at stage II or III, who underwent potentially curative resection between 1988 and 1998. Of these, 225 received post-operative administration of oral fluoropyrimidines such as UFT and 5'-DFUR, while the other 117 patients underwent surgery alone. Immunostaining for VEGF was performed using colorectal tumours. Overall, VEGF was positively expressed in primary tumour cells in 48% of patients. The disease-free survival rate and the overall survival rate in the chemotherapy group were higher than those in the surgery-alone group, although not significantly. However, the disease-free survival rate and the overall survival rate were similar between the two groups in patients with a tumour positive for VEGF. Multivariate analysis revealed that the VEGF expression was an independent factor for post-operative recurrence, and the VEGF expression and post-operative adjuvant chemotherapy were an independent factor for overall survival, in addition to the lymph node metastasis and the venous invasion. In conclusion, the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines may not be as great for patients with a tumour positive for VEGF having a greater risk of post-operative recurrence. The results support further investigation on efficacy of molecular targeting therapy for VEGF in combination with oral fluoropyrimidines as post-operative adjuvant therapy in colorectal cancer positive for VEGF.

Background/Aim: The aim of this study was to investigate the effects of preoperative chemotherapy on the healthy, metastasis-free part of the liver in colorectal cancer patients with liver metastasis, and the relationship between chemotherapy and postoperative complications. Patients and Methods: Our study included 90 cases of colorectal cancer liver metastasis resected after preoperative chemotherapy. The patients were divided into three groups according to the received chemotherapy regimen: 20 cases received mFOLFOX6, 54 cases a combination of mFOLFOX6 with bevacizumab, and 16 cases a combination of mFOLFOX6 and cetuximab or panitumumab. Results: The mean numbers of sinusoidal injuries for each chemotherapy type were compared. The group treated with the combination of mFOLFOX6 and bevacizumab showed a lower extent of sinusoidal injury relative to other groups; this intergroup difference became increasingly remarkable as the number of chemotherapy cycles increased. Complications of various extents were found in all three groups, but no significant differences were observed between the three groups. Conclusion: In cases where preoperative chemotherapy was extended over a long period, combined use of bevacizumab was thought to be effective because of stabilization of disturbed liver hemodynamics resulting from sinusoidal injury suppression effects, allowing effective distribution of anti-cancer agents to tumors. Colorectal cancer is one of the most frequently occurring malignant tumors worldwide (1). Approximately 60% of colon cancer patients have been reported to have complications of liver metastasis during the course of their disease (2). Surgical treatment presents the only possibility of curative treatment for colorectal cancer liver metastasis and has a strong impact on prognosis. A variety of efforts in recent years including preoperative liver function evaluation, preoperative chemotherapy, surgical procedures, preoperative management, and so on, have been reported to improve prognosis and liver resectability. Still, the major factor is the burden of chemotherapy itself (3-7). It has been reported (8) that, in cases where radical resection is possible, colorectal cancer liver metastasis shows approximately 60% recurrence, 80% of which are unresectable. Thus, chemotherapy will certainly play an increasingly important role in the future. Preoperative chemotherapy for colorectal cancer liver metastasis plays an important role in a regimen of multidisciplinary treatment. Chemotherapy also involves tissue adverse effects, and there are apprehensions regarding the effects on remnant liver when hepatectomy is performed following systemic chemotherapy (9). Veno-occlusive disease (VOD) (10), also known as sinusoidal obstruction syndrome (SOS), is a pathology that causes injury to sinusoidal and venule endothelial cells and is reported to be caused by radiotherapy, chemotherapy, and so on. Numerous reports have stated that SOS incidence is high in chemotherapy for colorectal cancer liver metastasis, especially in re...