M. Kilian

Does Dietary α-Linolenic Acid Promote Liver Metastases in Pancreatic Carcinoma Initiated by BOP in Syrian Hamster?

Background: α-Linolenic acid (ALA) has been shown to have a promoting effect on pancreatic carcinogenesis. The purpose of this study was to evaluate the influence of ALA on liver metastases in a model of BOP-induced pancreatic ductular carcinoma in the Syrian golden hamster. Methods: While the control group (group V) received a standard diet low in fat (soya oil, 3 w/v) without ALA, groups I–IV were fed a diet high in fat (soya oil 25 w/v) with increasing percentages of ALA (2.5, 5, 7.5 and 10%) for 16 weeks. Results: No significant differences in mean body weight and pancreas weight were found between the groups. But significant differences (p = 0.0001) were observed in the mean weight of the resected liver. Treatment with BOP alone resulted in the induction of well-differentiated ductal pancreatic adenocarcinoma in 91%, while all groups treated with different amounts of ALA had induction of 100%. The incidence of liver metastases differed significantly between the groups. The incidence of liver metastases in group I (2.5% ALA) was 18%, in group II (5% ALA) 27%, in group III (7.5% ALA) 50%, and in group IV (10% ALA) 91%. Moreover, the diameter of liver metastases increased significantly according to ALA supplementation (p = 0.001). Conclusion: The results indicate that dietary ALA increases liver metastases in BOP-initiated pancreatic cancer.

Local and systemic chemotherapy with taurolidine and taurolidine/heparin in colon cancer-bearing rats undergoing laparotomy

Experimental studies in the therapy of malignant abdominal tumors have shown that different cytotoxic agents suppress the intraperitoneal tumor growth. Nevertheless, a general accepted approach to prevent tumor recurrences does not exist. Following subcutaneous and intraperitoneal injection of 104 colon adenocarcinoma cells (DHD/K12/TRb), the influences of both taurolidine or taurolidine/heparin on intraperitoneal and subcutaneous tumor growth was investigated in 105 rats undergoing midline laparotomy. The animals were randomized into 7 groups and operated on during 30 min. To investigate the intraperitoneal (local) influence of either taurolidine or heparin on tumor growth, the substances were applied intraperitoneally. Systemic and intraperitoneal effects were evaluated after intravenous injection of the substances. Both application forms were also combined to analyze synergistic effects. Tumor weights, as well as the incidence of abdominal wound metastases, were determined four weeks after the intervention. In order to evaluate the effects of the agents, blood was taken to determine the peripheral leukocytes counts. Intraperitoneal tumor growth in rats receiving intraperitoneal application of taurolidine (median 7.0 mg, P=0.05) and of taurolidine/heparin (median 0 mg, P=0.02) was significantly reduced when compared to the control group (median 185 mg). The simultaneous instillation of both agents also reduced the intraperitoneal tumor growth (median 4 mg, P=0.04), while the intravenous injection of the substances caused no local effect. In contrast, the subcutaneous tumor growth did not differ among all groups. In all groups, abdominal wound recurrences were rare and did not differ. Independent of the agents and the application form, the operation itself caused a slight leukopenia shortly after the operation and a leukocytosis in the following course. Intraperitoneal therapy of either taurolidine or in combination with heparin inhibits local tumor growth and abdominal wound recurrences in rats undergoing midline laparotomy. Neither the intraperitoneal nor the intravenous application or the combination of the two agents influenced the subcutaneous tumor growth. The substances did not alter the changes of peripheral leukocytes.

Effects of Celebrex and Zyflo on BOP-Induced Pancreatic Cancer in Syrian Hamsters

Background/Aims: Selective inhibition of eicosanoid synthesis decreases inflammation, however, it is still unknown whether oxidative stress and carcinogenesis might be influenced in ductal pancreatic ductal cancer as well. Methods: 120 male hamsters were randomized into 8 groups (n = 15). While control group 1–4 received 0.5 ml normal saline s.c. weekly for 16 weeks, groups 5–8 were injected 10 mg BOP/kg body weight to induce pancreatic cancer. After establishment of pancreatic cancer, groups 1 and 5 received no therapy, groups 2 and 6 were fed 7 mg Celebrex daily, groups 3 and 7 were given 28 mg Zyflo and groups 4 and 8 received Celebrex and Zyflo orally daily in weeks 17–32. In week 33, all animals were sacrificed, macroscopic size of pancreatic carcinomas was measured, incidence of pancreatic cancer was analyzed histopathologically and activities of antioxidative enzymes and concentration of products of lipid peroxidation in tumor-free and pancreatic intratumoral tissue were determined. Results: Incidence and size of macroscopic pancreatic carcinomas were decreased by single therapy with Zyflo as well as combined therapy (Zyflo + Celebrex). Activities of antioxidative enzymes were increased and the concentration of products of lipid peroxidation was decreased in tumor-free pancreas. On the other hand, lipid peroxidation was increased in pancreatic tumors. Conclusion: Zyflo alone or in combination with Celebrex reduce tumor growth in pancreatic cancer and thus might be a new therapeutic option in advanced pancreatic cancer.

Influence of Octreotide on Liver Metastasis and Hepatic Lipid Peroxidation in BOP-Induced Pancreatic Cancer in Syrian Hamsters

Introduction In prospective clinical trials, octreotide improved quality of life and survival time in patients with pancreatic cancer. Aims To analyze whether octreotide modulates the hepatic oxygen radical metabolism and thus might decrease liver metastasis in an animal model of pancreatic cancer. Methodology Syrian hamsters received 0.9% NaCl or N-nitrosobis(2-oxopropyl)amine (BOP) for 3 months. Therapy was performed for 12 weeks by 0.9% NaCl or octreotide. Hamsters received a standard diet (3.5% fat) or were fed a high-fat diet (21.4% fat). In the 25th week, the pancreas and liver were examined macroscopically and histologically. The level of lipid peroxidation and activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were determined intrahepatically. Results The number of liver metastases per animal and the size of liver metastases were increased by the highfat diet, whereas they were decreased by octreotide. Octreotide increased activities of GSH-Px and SOD. The concentration of thiobarbituric acid reactive substances was increased by BOP and a high-fat diet and decreased by octreotide. Conclusion Octreotide decreases the number and size of liver metastases in chemically induced pancreatic cancer in Syrian hamsters. This is accompanied by high hepatic GSH-Px and SOD activity and a low level of lipid peroxidation.

Effects of octreotide in acute hemorrhagic necrotizing pancreatitis in rats

Background and Aim:  Octreotide is considered to reduce exocrine pancreatic secretion in acute hemorrhagic necrotizing pancreatitis decreasing pancreatic autodigestion. The aim of this study was to determine whether octreotide also has antioxidative effects in acute pancreatitis. Additionally time and dose of application were of interest.

Effects of the antioxidative vitamins A, C and E on liver metastasis and intrametastatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters.

Background/Aims: Antioxidative vitamins are known to inhibit metastasis. Therefore we evaluated the impact of vitamins A (retinol), C (ascorbic acid) and E (α-tocopherol) on liver metastasis in a model of ductal pancreatic adenocarcinoma in hamster. Methods: One hundred and twenty male Syrian hamsters were randomized into 8 groups (Gr.) (n = 15). Gr. 1–4 were given 0.5 ml normal saline subcutaneously (s.c.) weekly, whereas Gr. 5–8 received 10 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body weight s.c. for 3 months for tumor induction. In the 13th week Gr. 2 and 6 were administered retinol, Gr. 3 and 7 received ascorbic acid and Gr. 4 and 8 were given α-tocopherol orally. No treatment was performed in Gr. 1 and 5. After 24 weeks animals were sacrificed, pancreas and liver were histologically determined. Activities of glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD) and concentration of thiobarbituric-acid-reactive substances (TBARS) were analyzed in hepatic tissue. Results: Retinol and α-tocopherol decreased the incidence of liver metastases (44.4 vs. 86.7%, p < 0.05). The number and size of liver metastases were significantly reduced by retinol. Activities of GSH-Px and SOD were increased and concentration of TBARS was decreased in NML and LiMe by all vitamins. Conclusion: Obviously, antioxidative vitamins prevent oxidative stress in hepatocytes. This may be one mechanism decreasing liver metastasis in pancreatic cancer in the present trial.

Influence of Different Dietary Fat Intake on Liver Metastasis and Hepatic Lipid Peroxidation in BOP-Induced Pancreatic Cancer in Syrian Hamsters

Objectives: Effects of polyunsaturated fatty acids (PUFA) on carcinogenesis are discussed controversially. Thus, tumor growth seems to be influenced by type and composition of fat dietary; however, the pathomechanism is still unknown. Therefore, we investigated the impact of different PUFAs on liver metastasis and hepatic lipid peroxidation in a solid model of ductal pancreatic cancer in Syrian hamsters. Methods: 90 male hamsters were randomized into 6 groups (n = 15). Accordingly groups 2, 4 and 6 received 10 mg N-nitrosobis-2-oxopropylamine (BOP)/kg body weight weekly by subcutaneous injection for 12 weeks in order to induce ductal pancreatic cancer, while groups 1, 3 and 5 were treated with 0.5 ml 0.9% sodium chloride. All hamsters received a standard fat diet (SFD) rich in n–6 PUFA for 16 weeks (2.9% fat). Afterwards, groups 1 and 2 had free access to SFD, while groups 3 and 4 were given a diet enriched with n–3, n–6 and n–9 PUFA (SMOF) and groups 5 and 6 were fed a diet high in n–3 PUFA (FISH-OIL). After 32 weeks all hamsters were sacrificed in order to determine incidence of pancreatic carcinoma and liver metastasis. Furthermore hepatic activities of glutathionperoxidase (GSH-Px) and superoxiddismutase (SOD) as well as levels of lipidperoxidation were analyzed intra- and extrametastatically. Results: The incidence of liver metastasis was decreased in the FISH-OIL tumor group compared to the SFD and SMOF groups. However, GSH-Px activity was not influenced by different diets. Extrametastatic hepatic SOD activity did not differ between all groups, while intrametastatic hepatic SOD activity in the SFD-BOP group was increased. In the FISH-OIL-BOP and the SMOF-BOP group intrametastatic SOD activity was lower than in non-metastatic hepatic tissue. Furthermore levels of hepatic lipid peroxidation were decreased in the tumor groups treated with fish oil and SMOF compared to the SFD group. Comparing intra- and extrametastatic TBARS concentration there was no difference in the SFD-BOP and the SMOF-BOP groups, while in the FISH-OIL-BOP group intrametastatic TBARS concentration was increased. Conclusion: Conclusively, fish oil reduced the incidence of liver metastasis in experimental ductal pancreatic cancer. Maybe this effect is caused by an increase of intrametastatic hepatic lipid peroxidation.

Impact of taurolidin and octreotide on liver metastasis and lipid peroxidation after laparoscopy in chemical induced ductal pancreatic cancer

SummaryBackground: There is controversial discussion whether metastasis initiated by laparoscopy with carbon dioxide might be prevented by instillation of taurolidin or radical scavengers like the somatostatin analogue Octreotide. Therefore we evaluated the effects of laparoscopic lavage with taurolidin and Octreotide on liver metastasis after staging laparoscopy in ductal pancreatic cancer. Methods: In 60 Syrian hamsters pancreatic adenocarcinoma was induced by weekly subcutanous injection of 10 mg N-nitrosobis-2-oxopropylamin/kg body weight for 10 weeks. In the 16th week laparoscopic staging biopsy by use of carbon dioxide was performed. Finally animals underwent abdominal irrigation with saline (gr.1, n = 20), taurolidin (0.5%) (gr.2, n = 20) or Octreotide (gr.3, n = 20). In week 25 animals were sacrificed, pancreas and liver were analysed. Results: Size of pancreatic carcinomas was decreased in the taurolidin gr. compared to the other two groups. Furthermore the number of liver metastasis per animal was reduced after lavage with taurolidin (2 ± 2) and Octreotide (2.5 ± 2) compared to saline irrigation (4 ± 4) (p < 0.05). Additionally the incidence of port site metastases was significantly reduced in the taurolidin group. Activity of antioxidative enzyme superoxide dismutase (SOD) was increased while concentration of products of lipidperoxidation was decreased in non-metastatic liver after taurolidin irrigation compared to saline or Octreotide irrigation. Conclusions: Taurolidin irrigation during laparoscopy might be a new concept to reduce the number of liver metastasis and port site metastases in pancreatic cancer.

Early inhibition of prostaglandin synthesis by n-3 fatty acids determinates histologic severity of necrotizing pancreatitis.

Objective: Previously, we observed decreased histopathological severity of acute necrotizing pancreatitis (ANP) by parenteral nutrition with n-3 fatty acids. Thus, we now sequentially analyzed the impact of n-3 fatty acids on prostaglandin and leukotriene synthesis in ANP. Methods: One hundred ninety-eight Sprague-Dawley rats (11 groups, n = 18) underwent intraductal glycodesoxycholat instillation and 6-hour cerulein infusion. Afterward, saline was infused in groups 2, 4, 6, 8, and 10, whereas groups 3, 5, 7, 9, and 11 received infusion rich in n-3 fatty acids (Omegaven, Fresenius Kabi, Bad Homburg, Germany). Animals were killed after 6 (group 1), 10 (groups 2 and 3), 14 (groups 4 and 5), 18 (groups 6 and 7), 22 (groups 8 and 9), and 26 hours (groups 10 and 11). The pancreas was histopathologically examined, and the pancreatic eicosanoid metabolism (prostaglandin E2, prostaglandin F1&agr; [PGF1&agr;], and leukotrienes) and lipid peroxidation (thiobarbituric acid-reactive substance, superoxide dismutase, and glutathione peroxidase) were analyzed. Results: Between the 14th and 26th hours, histopathologic scores (edema, inflammation, bleeding, and necrosis) were reduced in the n-3 fatty acid group compared with the corresponding saline group. Pancreatic prostaglandin E2 and PGF1&agr; were decreased between the 10th and 18th hour by n-3 fatty acids; PGF1&agr; was reduced after 26 hours compared with the corresponding saline group. Lipid peroxidation was decreased by n-3 fatty acids after 14 hours (thiobarbituric acid-reactive substance); however, there was no difference concerning lipid peroxidation protective enzymes (glutathione peroxidase and superoxide dismutase). Conclusions: Parenteral therapy with n-3 fatty acids decreased histopathologic severity in ANP by early inhibition of prostaglandin (E2 and F1&agr;) synthesis and reduction of lipid peroxidation.

Influence of conjugated and conventional linoleic acid on tumor growth and lipid peroxidation in pancreatic adenocarcinoma in hamster

Conventional linoleic acid (LA) is regarded as a promotor of carcinogenesis. However, the effect of its conjugated derivative on cancer is still unknown. Therefore we investigated the influence of conventional and conjugated LA on tumor growth and lipid peroxidation in a solid model of pancreatic adenocarcinoma in Syrian hamsters. 60 male hamsters were randomized in 4 groups (Gr.) (n=15). Gr. 1 and 2 received 0.5 ml 0.9% sodium chloride subcutaneously (s.c.) once a week while Gr. 3 and 4 were injected 10 mg N-nitrosobis-2-oxopropylamine (BOP)/kg body weight weekly for 12 weeks to induce pancreatic cancer. Gr. 1 and 3 received a diet containing conventional LA, Gr. 2 and 4 were fed a diet of conjugated LA. After 29 weeks all animals were sacrificed, pancreas was weighed and examined macroscopically and histologically. The level of lipid peroxidation and activities of glutathion peroxidase and superoxide dismutase were determined in tumor-free as well as in pancreatic carcinoma tissue. Different diets did not influence the incidence of pancreatic carcinoma, however, pancreas weight was increased by conjugated LA compared to conventional LA. Furthermore both diets decreased the activity of glutathion peroxidase and increased the level of lipid peroxidation in pancreatic intratumoral tissue. The content of conjugated LA in dietary did not influence pancreatic tumor growth in a solid model of pancreatic adenocarcinoma in Syrian hamsters.