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We found that striptease-positive mast cells were abundant in the invasive front of human colon adenocarcinoma by examining 30 cases. Because tryptase has been suggested to be the agonist proteinase for protease-activated receptor-2 (PAR-2), we investigated the effects of stimulation of PAR-2 by tryptase on the cell signaling and proliferation of DLD-1, a human colon carcinoma cell line. PAR-2 stimulation by tryptase induced the increase in [Ca(2+)](i), which was desensitized by the prior application of PAR-2 activating peptide (AP). The proliferative responses of DLD-1 to tryptase and PAR-2 AP were associated with the phosphorylation of MEK and MAP kinase. Inhibition of MEK by PD98059 completely inhibited the proliferation-enhancing effects of tryptase and PAR-2 AP as well as phosphorylation of MAP kinase. Moreover, tryptase and PAR-2 AP stimulated the production of prostaglandin E2 and the inhibition of prostaglandin synthesis by indomethacin or NS398 resulted in the complete inhibition of the proliferative responses to tryptase and PAR-2 AP. Furthermore, the tryptase-stimulated proliferation of DLD-1 was concentration-dependently inhibited by nafamostat mesilate, a specific inhibitor of tryptase. These results as a whole indicated that tryptase has proliferative effects on DLD-1 through cyclooxygenase- and MAP kinase-dependent manners acting on PAR-2 by its proteolytic activity.

Protease-activated receptor-2 (PAR-2) has been demonstrated to be highly expressed in the gastrointestinal tract. In the present study, we investigated the effects of PAR-2 stimulation on the cell signaling and proliferation of DLD-1, a human colon carcinoma cell line, in comparison with the PAR-1 stimulation. PAR-2 stimulation by agonist peptide SLIGKV concentration-dependently induced the increase in [Ca2+]i and the proliferation of DLD-1 whereas the inverse peptide LSIGKV did not. Trypin (10(-9) M), an agonist protease for PAR-2, also enhanced the proliferation of DLD-1. The proliferative response of DLD-1 to PAR-2 stimulation was associated with the transient phosphorylation of MEK and MAP kinase, but not p38 MAP kinase and JNK. Inhibition of MEK by PD98059 (50 microM) completely inhibited the proliferation-stimulating effects as well as the phosphorylation of MAP kinase induced by PAR-2 agonist peptide (100 microM) and trypsin (10(-9) M). The prolonged treatment with PAR-2 agonist peptide for more than one hour was required for the enhanced proliferative response, suggesting the existence of unknown long-lasting cooperative signaling with MAP kinase cascade. PAR-1 stimulation by the agonist peptide SFLLRN (100 microM) or thrombin (10(-8) M) produced Ca2+ signaling, however, the stimulation neither produced the cell proliferative response nor the activation of MEK-MAP kinase cascade. These results indicated that Ca2+ signaling induced by PARs activation was not enough for inducing the cell proliferation in DLD-1 cells and that stimulation of PAR-2 can induce the activation of MEK-MAP kinase cascade, leading to the growth promoting response.

Severe nausea and vomiting are common side effects of anti-cancer chemotherapy. 5-HT3 receptor antagonists have been used for the treatment of these gastrointestinal symptoms. The purpose of this study was to examine whether specific changes in serotonin dynamics occurred in the gastrointestinal tract in mice in which Colon-26 adenocarcinoma cells were injected s.c., especially after treatment with cisplatin. The serotonin content of the small intestine of mice inoculated s.c. with Colon-26 adenocarcinoma increased significantly 2 weeks after the inoculation of the tumor cells; this was associated with an increase in tryptophan hydroxylase activity and the number of enterochromaffin cells as compared with control mice. Intravenous injection of cisplatin significantly reduced the serotonin content in the small intestine of Colon-26 tumour-bearing mice but not in control mice. The spontaneous release of serotonin from isolated intestine was not different between Colon-26 tumour-bearing and control mice; however, pretreatment of mice with cisplatin induced two fold increases in serotonin release from duodenum, jejunum and ileum in Colon-26 tumour-bearing mice but not in control mice. These results indicate that a region-specific increase in the number of enterochromaffin cells is observed in the intestine of Colon-26 tumour-bearing mice, associated with an increase in the serotonin content and tryptophan hydroxylase activity. Cisplatin treatment induced the release of serotonin from affected enterochromaffin cells in the gastrointestinal tract, which may be related to the occurrence of nausea in clinical use.

Conventional therapy for colorectal carcinoma using 5-fluorouracil (5-FU) has shown limited antitumor action. The purpose of our study was to investigate synergistic antitumor effects of the streptococcal preparation of OK-432 and 5-FU, and to elucidate the mechanisms of interaction between the 2 agents in mice. Biochemical modulation of OK-432 and 5-FU were determined in vivo against colon-26 carcinoma. The concentration of 5-FU and its metabolites, and the activity of thymidylate synthase and thymidine kinase, respectively, were measured using cytosolic extracts of the tumors. Combination treatment with OK-432 produced a significant increase in intratumor 5-FU and 5-FU in RNA (F-RNA) concentrations, increased the thymidylate synthetase inhibition rate, and decreased thymidine kinase activity, as compared with the results observed in the control mice. These additive antitumor effects are obtained by use of the 2 agents; the mechanism of action is considered to be the suppression of both the de novo and the salvage pathway for DNA synthesis, along with the suppression of RNA synthesis.

Background: Although surgical resectability is an important prognostic factor, recurrences are commonly noted in advanced colorectal cancer patients, even after apparently curative surgery. Because such recurrences cannot be cured, better adjuvant chemotherapies are urgently required., Patients and Methods: We studied the effect of postoperative chemotherapy using 1-hexylcarbamoyl-5-fluorouracil (HCFU) oral administration with or without 5-fluorouracil (5-FU) infusion for curatively resected Stage II and III colorectal cancer. This study was prospectively randomized and controlled and 303 (95.6%) of 316 patients were determined to be candidates for statistical assessment. Group A received oral HCFU, 300 mg daily for 52 weeks beginning 2 weeks after surgery. Group B also received 5-FU intravenous injection, 333 mg/m2 body surface area/24 hours continuously for 72 hours beginning on postoperative day 0 and 6., Results: There were no differences in overall 5-year survival or disease-free survival between Groups A and B. Group B had better 5-year disease-free survival (47.6%) than Group A (42.9%) (p = 0.062) and significantly prolonged interval from surgery to recurrence (p = 0.003) for patients with lymph node metastasis. In contrast, group B had significantly shortened 5-year disease-free survival (p = 0.010) and increased recurrence rate in patients without lymph node metastasis., Conclusion: Inductive therapy with 5-FU in combination with oral HCFU is beneficial as adjuvant chemotherapy for advanced colorectal cancer with lymph node metastasis.

Extensive atrophy has been reported to occur in the thymus in a cancer-burden state but the mechanisms of this atrophy have not been fully elucidated. We investigated changes in the thymus in tumour-bearing mice inoculated with two subclones of the murine colon 26 adenocarcinoma cell line: clone 5 (non-cachectic) and clone 20 (cachectic). In clone 20 mice, body weights and thymocyte numbers decreased significantly compared with controls. Flow cytometric analysis of the thymocytes demonstrated that the frequency of single positive cells (CD4+ CD8- and CD4- CD8+) was significantly increased and that of double positive cells (CD4+ CD8+) was significantly decreased in clone 20 mice and, to a lesser extent, in clone 5 mice compared with controls. Serum levels of interleukin 6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly elevated. These results suggested that thymocyte apoptosis was accelerated in the cancer-cachectic state, and increased GM-CSF might be partly responsible for thymic atrophy.

We report a successfully treated case accompanied by portal venous gas, which was associated with splenic abscess due to penetration of colon cancer. In June, 1998, a 67-year-old Japanese man was referred to our hospital because of a continuous fever over 40 degrees C and portal venous gas detected by computed tomography (CT). CT revealed low density areas in the spleen and wall thickening of the descending colon next to the spleen. Barium-enema examination demonstrated an extrinsic filling defect in the splenic flexure of the colon. Splenectomy, resection of the pancreatic tail and left hemicolectomy were performed Histopathological studies showed moderately differentiated adenocarcinoma, which made a fistula at the bottom of the ulceration to the spleen. The postoperative course was uneventful. The portal venous gas was likely to have resulted from a bacterial infection in the portal venous systems secondary to the splenic abscess.

Fas ligand (FasL) belongs to the TNF superfamily. It is induced in activated lymphocytes and eliminates Fas-positive lymphocytes, resulting in the down-regulation of immune responses. FasL has also been detected in tissues other than lymphoid cells. We investigated the expression and function of FasL on human colon cancer cells. FasL mRNA was detected by RT-PCR in all six colon cancer cell lines tested and was not found on fibroblasts. FasL protein was detected in DLD-1, LoVo, HCT-116 and RPMI 4788 cells by immunohistochemical staining. DLD-1, LoVo and WiDr were cytotoxic against mouse T lymphoma cells which were transfected with human Fas receptor cDNA. The cytotoxicity was significantly enhanced by phorbol 12-myristate 13-acetate (PMA) and ionomycin. Our data suggest that the FasL expressed in human colon cancer cells may be regulated by endogenous factors in the microenvironment of the host and facilitates the escape from the host immune system.

Patients with cancer cachexia often suffer from psychiatric disorders. In the present study, we investigated the changes in monoaminergic activities in the brain in tumor-bearing mice with reference to the development of cachexia. Two clones, clone-5 (noncachectic clone) and clone-20 (cachectic clone), derived from the murine Colon-26 adenocarcinoma cell line (Nippon Roche Research Center), were inoculated subcutaneously at 1 x 10(6) cells/0.2 ml into the right lower back of BALB/c mice. In clone-20 mice, body weight and locomotor activity decreased significantly 10-15 days after tumor inoculation. The levels of noradrenaline, dopamine, and 3,4-dihydroxyphenylacetic acid showed no significant change among the three groups. The noradrenaline turnover rate in clone-20 mice was increased in cerebral cortex, hypothalamus, and midbrain. The 5-hydroxytryptamine turnover rate in clone-20 mice was increased in hippocampus, cerebral cortex, midbrain, and pons-medulla oblongata. In contrast, the dopamine turnover rate in clone-20 mice was decreased markedly in hippocampus, cerebral cortex, striatum, hypothalamus, and cerebellum. There was no significant change in amine turnover between control and clone-5 mice except for dopamine in hippocampus, cerebral cortex, and striatum and 5-hydroxytryptamine in striatum. No significant change in the levels of amino acids in the brain was observed among the three groups of mice. It is concluded that some of the psychiatric disorders from which cancer cachectic patients suffer might be ascribable to changes in monoaminergic activities in the brain.

Purpose: Mucocele of the appendix is an uncommon disorder, usually found incidentally during ultrasonography or radiographic studies. We report two cases of combined appendiceal mucocele and colonic cancer., Methods: The two cases were analyzed for the clinicopathologic characteristics such as history, presentation, laboratory data, radiologic and endoscopic studies, pathology, and p53 immunoreactivity., Results: Two patients were diagnosed with an appendiceal mucocele by ultrasound of the abdomen, together with computed tomography. Colonoscopic examination subsequently revealed synchronous colonic adenocarcinoma in both patients. Ileocecal resection following endoscopic polypectomy and a right hemicolectomy was performed for each patient. An appendiceal mucocele was histologically diagnosed as a mucinous cystadenoma. Immunohistochemical detection of abnormally high level of p53 protein was observed in colonic adenocarcinomas of both patients, whereas both appendiceal cystadenomas were negative for p53., Conclusions: To be remembered is the high frequency of concomitant gastrointestinal tumors in patients with appendiceal mucocele, especially caused by mucinous neoplasms. A total colonoscopic surveillance will afford earlier diagnosis of synchronous colonic cancers in these patients.

Cyclosporine A (CSA), an immunosuppressive agent with apparently selective effects on T lymphocytes and little myelotoxicity, was tested for its effects on hepatic metastases by inoculation of mouse colon-26 tumour cells into the portal vein in male CDF1 mice. CSA, given subcutaneously in daily doses of 10-50 mg/kg/day, for 22 days, significantly increased the incidence of hepatic nodules. This increase was positively correlated with the CSA dose. When 5-fluorouracil was injected at a dose of 15 mg/kg/day every other day after the inoculation of tumour cells a highly significant reduction in the incidence of metastases was seen (compared with the controls). This strong inhibitory effect of 5-fluorouracil on metastasis was almost completely suppressed when mice were treated with CSA concomitantly. The results suggest that CSA affects the host immune system, accelerating the production of hepatic metastases.

Eighteen (5.0%) out of 358 patients who underwent resection of a colorectal carcinoma during the period 1978 through 1990 had synchronous colorectal carcinomas, and were 5.6 years younger on average than those with a single carcinoma. The distance between synchronous lesions was less than 10 cm in 69.6% of all the patients in the study. Among the synchronous carcinomas there was a higher incidence of ascending colon involvement, mucinous carcinoma, family history of malignant diseases, multiple malignant neoplasms associated with other organs and benign neoplastic polyps of the colorectum, and it is suggested that hereditary oncogenic factors influence these carcinomas. The synchronous lesions were detected pre-operatively in 14 of 18 patients with synchronous carcinomas, and the most common reason why synchronous lesions were missed was that the lesions on the anal side prevented the lesions on the proximal side from being examined. The prognosis in the synchronous lesion group was worse than in the solitary lesion group. Since it is difficult to predict synchronous colorectal carcinomas, careful pre-operative examination, including that of other organs, is necessary, and intra-operative colonoscopy should be carried out when pre-operative examination was insufficient.

Although many agents that interfere with clotting mechanisms have been investigated for their potential to inhibit metastasis, their toxicity has prevented administration of sufficiently high doses to achieve inhibition of metastasis in clinical trials. Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, inhibited liver metastasis in a CDF1 mice model with colon 26 adenocarcinoma cells. The apparently dose-dependent inhibitory effect was seen 21 days after all of the doses tested (0.3, 1.0, 3.0 and 10.0 mg/kg for 7 days) but the effect was only statistically significant (P less than 0.01) at the highest dose. The blood concentrations 3 min after dosing were less than 10(-6) M for all of the doses tested. At a concentration of 10(-5) M or less nafamostat mesilate was not cytotoxic towards colon 26 cells in vitro. The results indicate that it may not be difficult to achieve blood nafamostat mesilate concentrations that inhibit metastasis in mouse liver. Possible mechanisms of nafamostat mesilate are inhibition of extravasation and invasion of cancer cells, inactivation of collagenase due to inhibition of plasmin activity and inhibition of the formation of the cancer cell thrombus, and arrest in the capillaries through inhibition of thrombin activity. These preliminary results suggest that peri-operative administration of nafamostat mesilate may prevent metastasis into the liver after surgery for gastrointestinal malignancies.

The tumor lysis syndrome, consisting of severe hyperkalaemia, hyperphosphatemia and hypocalcemia, occurs after the effective induction chemotherapy of rapidly growing responsive tumors. The metabolic abnormalities are thought to be secondary to the release of intracellular products. For the purpose to examine quantitative relation between cellular potassium release and drug sensitivity, we compare the inhibition of valinomycin (K-ionophore)-induced-hyperpolarization (MPR Test) with that of succinate dehydrogenase activity (SDI test). Our present research revealed a high correlation of MPR test and SDI test, and suggested the significant association of drug sensitivity with potassium release from cancer cells. Therefore, it seems appropriate to monitor potassium levels when therapy of a responsive tumor is initiated.

This study demonstrates that the cytotoxicity of FT-207 was potentiated with elevated temperatures. This result leads us to the hypothesis that the heat-produced superoxide radicals could metabolize and degradate FT-207 to 5FU at membrane or cytoplasm.