Biomedical subjects

T Tobe

Publications and source records attributed to T Tobe.

At least 181 records · Page 10Linked to original sources

PubMed1991

Role of free radical scavengers in pancreatic carcinomas of hamsters.

The involvement of free radicals in the carcinogenic mechanism has been suggested, however, little is known about the role of free radicals in the pancreatic cancer. In this study, the effects of active oxygen on the carcinogenesis of the tumor were examined by measuring the levels of scavengers in pancreatic cancer of Syrian golden hamsters. Pancreatic cancer was induced by di-iso-propanol nitrosamine (500 mg/kg body weight/week x 24 weeks). Activities of superoxide dismutase (SOD), catalase, glutathion peroxide (GSH-Px) and malon dialdehyde (MDA) in the tumor and border zone were compared with those in the non-tumor region and control normal tissue. Activities of SOD and catalase in the tumor and border zone were significantly lowered than those in non-tumor region and normal tissue. GSH-Px levels were significantly higher in the tumor than those in the non-tumor region and normal tissue. MDA levels also tended to be high in the tumor. These results suggest that the development of cancer in pancreatic tissue is related to a reduction of SOD and catalase. GSH-Px and MDA are suggested to be involved in the reactions of free radicals.

Animals↗

PubMed1991

A new synthetic protease inhibitor, E-3123, reduces organelle fragility of acinar cells in rat caerulein pancreatitis.

The present study investigated the protective effect of a new potent synthetic protease inhibitor, E-3123 (4-guanidinobenzoate methanesulfonate) on the exocrine pancreas in the caerulein induced experimental pancreatitis both in-vivo and in-vitro at 3 different doses (1, 2, and 5 mg/kg.hr). This protease inhibitor prevented hyperamylasemia, pancreatic edema, congestion of amylase, and both amylase and lactic dehydrogenase (LDH) discharge from dispersed acini, as well as cathepsin B leakage from lysosomes and malate dehydrogenase (MDH) leakage from mitochondria in a dose-dependent manner, particularly in doses of 2 and 5 mg/kg.hr. Furthermore, the combined prophylactic and therapeutic use of this agent seems to be very effective in preventing caerulein induced pancreatitis. These results indicate that E-3123 plays its protective roles against pancreatitis in the subcellular compartment: lysosomes, mitochondria, cellular or organella membranes. It is hoped that such a low molecular weight protease inhibitor as E-3123 will be clinically useful in the treatment of acute pancreatitis.

Acute Disease↗

PubMed1991

[Effect of synthetic protease inhibitor on the oncogenesis of pancreatic cancer in hamsters: study on pancreatic endocrine cells and free radicals].

In order to study the effect of synthetic trypsin inhibitor on the oncogenesis of pancreatic cancer, the histology, the kinetics of the B, A and D cells in the islets of Langerhans and activities of free radical scavengers, superoxide dismutase (SOD), glutathion peroxide (GSH-Px) and malon dialdehyde (MDA) in the tumor bearing tissues were measured in hamsters with pancreatic cancer induced by di-iso-propanol nitrosamine (DIPN) with or without camostat (FOY-305). In DIPN group (DIPN alone), the tubular adenocarcinoma was found in 80%, however, in FOY group (DIPN+FOY-305), papillary adenocarcinoma was found in 91%. In both DIPN and FOY groups, the number of B cells was decreased at 8 weeks and the number of A and D cells was decreased at 16 weeks. Activities of SOD in the tumor and borderzone in DIPN group were significantly lower than those in non-tumor region and normal tissue. However, activities of SOD in the tumor and borderzone in FOY group were higher than those in DIPN group. GSH-Px and MDH levels were significantly higher in FOY group suggesting the involvement in the reaction of free radicals. These results suggest that trypsin inhibitors have a prophylactic effect on the development of pancreatic cancer.

Animals↗

PubMed1991

[Changes of acinar cells in the pancreato-biliary duct ligation with exocrine pancreatic stimulation model in rats; protective effects of a new potent protease inhibitor, ONO3307].

To evaluate the changes of pancreatic acinar cells in the pancreatic duct obstructed animals as well as the protective effects of a new potent protease inhibitor, ONO3307, we measured the serum amylase levels, pancreatic water content, histological changes, lysosomal fragility in in-vitro incubation, cathepsin B distribution in acinar cells, and cathepsin B and amylase output into pancreatic juice after short-termed (3 hrs) pancreatic duct obstruction with caerulein (0.2 micrograms/kg.hr) infusion in rats. Serum amylase levels, pancreatic water content, and lysosomal fragility in duct obstructed with caerulein infused animals were significantly increased compared with the control groups, and remarkable shift of cathepsin B from lysosomal fraction to zymogen fraction was observed in this group. These changes tended to continue 24 hours after removal of duct obstruction. But with infusion of ONO3307, these changes observed in duct-obstructed with caerulein infusion groups were significantly, almost completely attenuated. These results indicate the intimate relationship between the pathogenesis of acute pancreatitis and lysosomes and some known proteases which are inhibited by ONO 3307 and suggest the usefulness of such a kind of protease inhibitor in the treatment of acute pancreatitis.

Acute Disease↗

PubMed1991

[Effect of oxygen free radicals on the rat pancreas in vivo].

Many reports concerning the involvement of active oxygen free radicals in the pathogenesis and progression of acute pancreatitis have been published. In this study, the direct toxic effect of active oxygen free radicals on the rat pancreas was evaluated in vivo. Superoxide anions, generated via the xanthine/xanthine oxidase (X/XO) system, and hydrogen peroxide (H2O2) were used. After continuous arterial injection of X/XO into the celiac artery hemorrhage and extensive edema developed. However, additional continuous injection of superoxide dismutase (SOD) into the external jugular vein completely suppressed the hemorrhage and relieved the edema. When hydrogen peroxide (100 microM/Kg/hour) was injected continuously through the celiac artery made hemorrhage and edema were recognized in the pancreas, both of which were suppressed by continuous injection of catalase (10 mg/Kg/hour) or gabexate mesilate (10 mg/Kg/hour) into the external jugular vein. The amylase and lipase levels in the intraperitoneal fluid rose to more than 10 times the preoperative values 5 hours after drug administration. These levels were lowered to 2 times the preoperative values by the continuous venous injection of SOD or catalase (which are specific scavengers of superoxide anions or hydrogen peroxide, respectively) or by gabexate mesilate. On the other hand, serum amylase and lipase levels remained almost constant throughout the entire experiment. Thus, the administration of active oxygen free radicals caused acute pancreatitis, which was suppressed by the systemic administration of specific scavengers for each free radical. Active oxygen free radicals were shown to have a direct, toxic effect on the pancreas.

Acute Disease↗

PubMed1991

[Effect of short-term-ischemia and reperfusion on the rat pancreas].

In order to examine the toxic effects on the pancreas of oxygen free radicals which are generated at reperfusion after ischemia, a short term-ischemia/reperfusion model was prepared in rats. Both the anterior mesenteric artery and the celiac artery were ligated and then released to restore blood flow. In a group where the anterior mesenteric and the celiac arteries were ligated for 60 minutes, the serum levels of amylase and lipase rose 7 and 6 times, respectively, 7 hours after reperfusion. In a group ligated for 30 minutes, both levels remained unchanged. Histologically, vacuolization of the pancreatic acinar cells was observed, only in a group rats ischemic for 7 hours. In rats ligated for 60 minutes with a continuous venous infusion of superoxide dismutase (SOD) (3600 U/Kg/hour), the secretion of amylase and lipase decreased to 25 percent of that in the non-injected group. These results confirm that the oxygen free radicals, which are generated by the short term-ischemia/reperfusion method, injure the pancreas. This may lead to pancreatitis with hyperamylasemia and hyperlipasemia. Pretreatment with an active oxygen scavenger, SOD, markedly reduces the rise in serum amylase and lipase levels. This suggests that active oxygen free radicals are involved in the pathogenesis of acute pancreatitis.

Acute Disease↗

PubMed1991

Isolation of two forms of decay-accelerating factor (DAF) from human urine.

Decay-accelerating factor (DAF) was purified from human pooled urine by conventional techniques. The urine DAF was separated into two peaks, pool I and pool II, by gel chromatography. DAF-U1 was isolated from pool I by hydrophobic chromatography, and DAF-U2 from pool II by anti-DAF IgG column. The specific activities of DAF-U1 and DAF-U2 to decay membrane-phase C5 convertase were about 3% and 70% of membrane form DAF, respectively. However, both urine DAFs revealed a similar activity to each other and slightly higher activity than that of membrane form DAF in decay-accelerating fluid-phase C3 convertase of the alternative pathway.

Amino Acid Sequence↗

PubMed1991

Changes of A, B and D cells in Langerhans islets in pancreatic cancers of hamsters.

In order to clarify the effect of pancreatic hormones on the oncogenesis of pancreatic cancer, the kinetics of the B, A and D cells in the islets of Langerhans were studied in hamsters with pancreatic cancer induced by di-iso-propanol nitrosamine (DIPN). Tumors appeared histologically 8 weeks and duct adenocarcinomas became evident 12 weeks after the administration of DIPN. Although the area of the islets did not change in 8 to 16 weeks, the numbers of B cells was decreased 8 weeks after the administration of DIPN and of A and D cells was decreased at 16 weeks. The area occupied by B cells in proportion to the number of islet cells showed a significant decrease 8 weeks after the administration of DIPN. Since insulin has been reported to have a trophic effect on the exocrine pancreas, our findings suggest that pancreatic B cells start to decrease at the same time that pancreatic cancer begins to form. Thus, insulin appears to play an important role locally in the oncogenesis of pancreatic cancer in acinar cells.

Animals↗

PubMed1991

Clinico-pathological features of liver metastases from colorectal cancer in relation to prognosis.

Twenty-nine patients undergoing hepatic resection for colorectal metastases from 1980 to 1986 were studied. The overall cumulative survival rates were 82%, 63% and 32% at 1, 2 and 3 years, respectively. The possible prognostic factors, i.e., Dukes' staging of the primary lesion, the number of metastatic nodes, synchronous versus metachronous appearance of metastases, and curative versus non-curative resection were estimated. Evaluation of those categories did not provide any significant information for prognosis after hepatic resection for liver metastases. The growth patterns of the tumor boundary were classified into three types as sinusoidal, expansive, and mixed. There was no significant difference in the survival rates among these groups. The significant factor affecting prognosis was only whether the secondary tumors were encapsulated or not. Patients with encapsulated tumor of the interval longer than 2 years between colon resection and hepatic resection had a significantly better survival rate.

Adult↗

PubMed1991

Deletion of 17p and amplification of the int-2 gene in esophageal carcinomas.

We have analyzed allelic deletion at 23 loci on 18 different chromosomes in 35 esophageal squamous cell carcinoma tissues by using restriction fragment length polymorphism markers. Loss of heterozygosity was detected on chromosomes 2, 3, 6, 7, 11-14, 16-18, 21, and 22, while no loss was detected on chromosomes 1, 4, and 8-10. Only the loss of chromosome 17p was detected with high frequency (45%), and losses on other chromosomes had frequencies of less than 22%. These losses with low frequencies might be random losses caused by chromosomal rearrangement during the course of tumor development and progression. On the contrary, the loss of 17p might play an important role in the development of esophageal squamous cell carcinoma, such as inactivation of a tumor suppressor gene. Amplification of the int-2 gene was observed in 39% of the tumors. However, no significant relationship between int-2 amplification and the deletion of any chromosome was detected.

Aged↗

PubMed1991

Tissue distribution of 2-3 and 2-6 sialyl Lewis A antigens and significance of the ratio of two antigens for the differential diagnosis of malignant and benign disorders of the digestive tract.

The authors investigated the tissue distribution of two kinds of sialylated derivatives of Lewis A (Le(a)) antigen in patients with cancers of the digestive system using specific monoclonal antibodies, and evaluated the significance of determining the 2-3 and 2-6 sialylated Le(a) antigen levels for the diagnosis of cancer. In most specimens from patients with cancers of the pancreas, biliary tract, stomach, and colon, the 2-3 sialylated Le(a) antigen was strongly expressed in cancer cells. However, 2-6 sialylated Le(a) antigen was less frequently expressed in cancer cells. The former is therefore more specific to cancer than the latter. Also, the serum level of the 2-3 sialylated Le(a) antigen was significantly higher than that of the 2-6 counterpart in patients with cancers of pancreas, biliary tract, stomach, and colon. The resulting ratio of serum 2-3/2-6 sialylated Le(a) antigens was frequently high in patients with malignancy and was low in patients with benign disorders of these digestive organs. Therefore, the 2-3/2-6 sialylated Le(a) antigen ratio is a useful for the differential diagnosis of malignant disorders in these organs. However, liver disorders were found to be exceptional in that both antigens were mostly absent in hepatocellular carcinoma (HCC) cells in immunohistologic examination, as well as in nonmalignant parenchymal liver cells. Only the epithelial cells of the intrahepatic bile ducts expressed the 2-6 sialylated Le(a) antigen strongly, and expressed the 2-3 sialylated Le(a) antigen moderately. The levels of both antigens were sometimes high in patients with liver disorders, but the ratio always remained low in patients with HCC as well as benign liver disorders such as cirrhosis or chronic hepatitis. The sialylated Le(a) antigens, which sometimes accumulate in the sera of patients with HCC, were concluded to originate from the epithelial cells of the proliferating small bile ducts, and those serum antigens cannot be considered as evidence for the presence of liver cancer cells.

Antibodies, Monoclonal↗

PubMed1991

[Changes of lysosomal and digestive enzymes in rat caerulein pancreatitis].

We evaluated the changes of lysosomal and digestive enzymes in the exocrine pancreas after caerulein induced acute pancreatitis in rats. The serum amylase levels and water content as well as pancreatic amylase and cathepsin B contents increased significantly in the early stage (0-12 h) after caerulein was administered, however, returned to the normal levels at 36 h. In the early stage, colocalization of lysosomal enzyme and digestive enzyme was found. Histologically, in the early stage, there were remarkable changes such as acinar cell vacuolization and interstitial edema, but these changes disappeared at 36 h. Furthermore, amylase and cathepsin B outputs decreased significantly in the early stage (12 h) but at 24 h, these increased significantly. LDH discharge from dispersed acini and cathepsin B leakage from lysosomes also increased in the early stage (0-12 h), but these values returned to the normal levels at 36 h. These results indicate that exocrine pancreas needs about 36 h to recover from the caerulein induced acute pancreatitis, and in this recovering process, secretion of colocalized digestive enzyme and lysosomal enzyme seem to play an important role.

Acute Disease↗

PubMed1991

Problems in the definition and treatment of early gastric cancer.

Radical operation with extensive dissection of lymph nodes (R1, 48 patients; R2, 196 patients; R3, one patient) was performed in 245 out of 247 patients with early gastric cancer. The 5-year survival rate was only 73.2 per cent in the 34 patients with lymph node metastases (31.8 per cent). Analysis of factors influencing recurrence revealed that not only lymph node metastases but also the depth of cancer invasion could affect prognosis in early gastric cancer. This study suggests that radical operation with complete dissection of the first and second group of lymph nodes (R2 resection) is a safe and appropriate treatment even for early gastric cancer. We propose that the definition of early gastric cancer be modified to 'carcinoma with invasion confined to the mucosa or submucosa and without evidence of lymph node metastases'.

Female↗

PubMed1991

Effects of splenectomy on pulmonary metastasis and growth of SC42 carcinoma transplanted into mouse liver.

The carcinoma SC42 was transplanted into the liver of its syngeneic mice DS, and the immunological integrity of the spleen and the effects of splenectomy on the growth and pulmonary metastasis of the liver tumor were assessed. On day 7 after liver tumor transplantation, the natural killer (NK) activity of the splenocytes was significantly elevated; it subsequently decreased at a later stage of the tumor. The response of the splenocytes to PHA and Con-A decreased significantly from the early stage of the tumor. However, the mixed lymphocyte-tumor cell reaction increased significantly from day 14 to day 28. The survival rate of the mice, which had undergone simultaneous splenectomy and liver tumor transplantation, was significantly lower than that of sham-operated control mice. The number of pulmonary metastases in splenectomized mice was significantly greater than in the control mice. There was, however, no difference between the two groups in the weight of the liver tumor. By contrast, splenectomies performed 14 days before or 14 days after tumor transplantation had no significant influence on the survival of the mice. Splenectomies performed on day 0 and on day 3 after tumor transplantation significantly increased the number of pulmonary metastases. Furthermore, the intravenous injection of anti-asialo GM1 antisera on day 0 and day 3 significantly increased the number of pulmonary metastases, but injection of anti-Thy 1.2 antisera had no effect. These results suggest that splenic NK cells may play an important role in the suppression of pulmonary metastasis at early stages of the liver tumor.

Animals↗

PubMed1991

Combining independently effective anticancer agents may not augment the independent antitumor effects: a study using human digestive organ cancer xenograft lines in nude mice.

Five human digestive organ cancer xenograft lines were subcutaneously transplanted in nude mice, and 7 anticancer agents (ACAs) were intravenously administered singly or in combinations at 4 times the standard clinical doses. Cisplatin (P) was effective in 4 lines and 5-fluorouracil (F) was effective in 3 lines. A total of 8 combinations with 2 effective ACAs were assessed in 4 lines and only 1 combination (FP) resulted in an augmented antitumor effect in a single line. A total of 11 combinations with 1 effective ACA plus 1 ineffective ACA were assessed in 2 lines, and only 1 combination (F + carboquone [CQ; Esquinon]) resulted in an augmented effect in a single line. A total of 5 combinations with independently ineffective ACAs were assessed in 1 line, and 1 combination (FP) resulted in augmented antitumor activity. No 2-ACA combinations showed enhanced side effects. Two combinations with 3 effective ACAs were assessed in 2 lines and 1 combination (FP + mitomycin C) resulted in an augmented effect with a greater mortality rate. A total of 12 combinations with both effective plus ineffective ACAs were assessed in 2 lines, and 3 combinations (FP + Adriamycin or FP + CQ or FP + etoposide) resulted in an augmented effect in 1 line with enhanced side effects. These results indicate that the combination of independently effective ACAs does not always cause an augmented antitumor effect, and may sometimes result in augmented side effects. According to this study, the 3-ACA combinations with FP + 1 effective agent appear to be the best regimens for digestive organ cancer.

Animals↗

PubMed1991

In vitro immunomodulating effect of protein-bound polysaccharide, PSK on peripheral blood, regional nodes, and spleen lymphocytes in patients with gastric cancer.

PSK, a protein-bound polysaccharide, has been widely used for cancer immunotherapy in Japan. However, the mechanism of its immunomodulatory effect has not been fully clarified. In the present study the in vitro effect of PSK on the lymphocytes of patients with gastric cancer was studied. Culturing lymphocytes with PSK at 5-100 micrograms/ml increased the level of DNA synthesis, and augmented the cytotoxicities against K562 and KATO-3. Flow-cytometric analysis also showed an increase in the proportion of interleukin-2 (IL-2)-receptor-positive cells after the lymphocytes were cultured with PSK. However the cytotoxicity of cells cultured with PSK was not augmented by the addition of recombinant interferon gamma (rIFN gamma) and rIL-2. Further experiments using fractionated PSK showed that its biological action is present mainly in fractions having molecular masses greater than 10(5) Da. However, these immunomodulations were not seen in all patients. These results suggest that the susceptibility of lymphocytes to PSK may be different in each patients, and that the immunomodulation by PSK may be mediated by mechanisms independent of IFN and IL-2.

Adjuvants, Immunologic↗

PubMed1991

A murine plasmacytoma MOPC 104E resistant to cyclophosphamide is resistant to immunotherapy.

A murine plasmacytoma MOPC 104E (MOPC) is highly sensitive to chemotherapeutic agents such as cyclophosphamide and mitomycin C as well as to immunotherapy (OK-432-combined adoptive immunotherapy using interleukin-2-cultured killer cells). In the present study, we prepared cyclophosphamide-resistant MOPC cells (MOPC-CPA/R) by serial in vivo passage of tumor cells following cyclophosphamide treatment. The in vivo sensitivity of MOPC-CPA/R to mitomycin C or to immunotherapy (OK-432-combined adoptive immunotherapy) was significantly decreased compared to the parent MOPC. In vitro experiments showed that MOPC-CPA/R were more resistant (five-fold) to lysis by cultured immune spleen cells than MOPC. Inhibition of the lytic activity of cultured immune spleen cells against MOPC was significantly increased (P less than 0.05) by the addition of unlabeled MOPC compared to unlabeled MOPC-CPA/R. These results suggest that MOPC-CPA/R express weaker antigenicity than MOPC. However, the transfer of immune spleen cells cultured with tumor extract derived from MOPC-CPA/R significantly prolonged the survival of MOPC-CPA/R-inoculated mice. Thus, by repeated cyclophosphamide treatment, tumor cells with low-antigenicity were selected. These tumor cells had lower sensitivity to another chemotherapeutic agent and immunotherapy. Such an immunological response may play an important role in cancer therapy.

Animals↗

PubMed1991

In vivo effects of human recombinant tumor necrosis factor alone and in combination with other biological response modifiers on human digestive organ cancer xenografts transplanted in nude mice.

The present study was designed to evaluate the effect of rTNF alone or in combination with other BRMs on human digestive organ cancers. Six kinds of human digestive organ cancer xenografts (esophageal, stomach, colonic, pancreatic, bile duct, and liver cancers: EC-YO, GC-YN, CC-KK, PC-HN, BDC-SN and Li-7, respectively) were transplanted in nude mice, and rTNF was administered at 10(3), 5 x 10(3), or 10(4)U/head directly into the tumor 3 times a week for 2 weeks. EC-YO was the most sensitive to rTNF, and intratumoral administration of rTNF at 10(3) U/head caused tumor regression. PC-HN, CC-KK and GC-YN were relatively sensitive to rTNF, and their growth was significantly inhibited by rTNF at 5 x 10(3) U/head, however, the tumors regrew after treatment. Li-7 and BDC-SN were resistant to rTNF. The effects of rTNF in combination with recombinant interferon-gamma (rIFN-gamma), recombinant interleukin-2 (rIL-2), or streptococcal preparation OK-432 were assessed in mice transplanted with GC-YN. All combinations of rTNF at 5 x 10(3) U/head and other BRMs were more effective than rTNF alone, and GC-YN tumors were completely regressed after treatment with a combination of rTNF and rIFN-gamma or rTNF and OK-432. However in all cases, the combination of rTNF at 10(3) U/head and any other BRM did not improve the effect. Furthermore, the adverse effects of the combinations were more serious than those of rTNF alone. TNF may still be a useful cytokine, because it can induce the regression of tumors. However, for its clinical application, a method should be developed to reduce its side effects.

Animals↗