Effects of taurolidine and octreotide on tumor growth and lipid peroxidation after staging-laparoscopy in ductal pancreatic cancer

Irrigation with taurolidine after laparoscopy decreases tumor growth in colon carcinoma. In pancreatic cancer subcutaneous therapy with octreotide decreases oxidative stress and carcinogenesis as well. However, it is still unclear, whether irrigation with taurolidine or octreotide after laparoscopic pancreatic biopsy reduces tumor growth in pancreatic cancer as well. In 60 Syrian hamsters ductal pancreatic adenocarcinoma was induced by weekly injection of 10mg/kg body weight N-nitrosobis-2-oxopropylamine s.c. for 10 weeks. In week 16 laparoscopic pancreatic biopsy by use of carbon dioxide was performed (gr. 1, n = 20) with subsequent laparoscopic irrigation with taurolidine (gr. 2, n = 20) or octreotide (gr. 3, n = 20). In week 25 hamsters were sacrificed. Our results show that macroscopic visible primary tumors were found in only one animal of the taurolidine group (5.9%), compared to 42.1% in the saline and 62.5% in the octreotide group (P<0.05). Carcinomas were smaller after saline (6+/-23 mm(2)) than after octreotide irrigation (70+/-120 mm(2), P<0.05). In conclusion this study showed that laparoscopic irrigation with taurolidine after pancreatic biopsy inhibited tumor growth in ductal pancreatic adenocarcinoma.     

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.     

The persistence of DNA damage in the pancreas of Syrian golden hamsters treated with N-nitrosobis(2-oxopropyl)amine

DNA damage was estimated in the liver, pancreas and salivary gland of Syrian hamsters given N-nitrosobis(2-oxopropyl)amine (BOP) by alkaline sucrose gradient centrifugation. A single BOP dose (10 mg/kg) produced in all 3 tissues extensive DNA damage that was largely repaired in the salivary gland by 4 weeks, while in the liver and pancreas, some DNA damage persisted until 4 weeks. When higher BOP doses (20 and 40 mg/kg) were used, considerable DNA damage was still evident in the pancreas, but not in the liver at 6 weeks. Greater damage persisted in hamsters given 40 mg/kg, compared with those administered 20 mg/kg.     

Impact of polyunsaturated fatty acids on hepato-pancreatic prostaglandin and leukotriene concentration in ductal pancreatic cancer—Is there a correlation to tumour growth and liver metastasis?

Type and composition of polyunsaturated fatty acids (PUFAs) are suspected to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 PUFAs on tumour growth, liver metastasis and concentration of prostaglandins (PG) and leukotrienes (LT) in experimental ductal pancreatic adenocarcinoma. Ninety male hamsters were randomised into six groups (Gr.) (n=15). While Gr. 1-3 were healthy control groups, Gr. 4-6 weekly received subcutaneous injections of 10mg N-nitrosobis-2-oxypropylamine (BOP)/kg body weight for 12 weeks in order to induce ductal pancreatic adenocarcinoma. Between week 1 and 16 all animals were fed with a standard diet with a raw fat content of 2.9%. In week 17 Gr. 1-6 were allocated to three types of diets: Gr. 1: standard high fat (=SHF diet, rich in n-6 PUFAs)/Gr. 2: FISH-OIL (rich in n-3 PUFAs)/Gr. 3: SMOF (=mixture of n-3, n-6 and n-9 PUFAs)/Gr. 4: BOP+SHF/Gr. 5: BOP+SMOF/Gr. 6: BOP+FISH-OIL. After 32 weeks all animals were sacrificed and pancreas as well as liver were analysed histologically. Furthermore pancreatic and hepatic concentrations of prostaglandins (PGF1alpha, PGE(2)) and LT were measured. FISH-OIL decreased number of macroscopically visible pancreatic tumours (Gr. 4-6: 54.5% vs. 45.5% vs. 9.1%, P<0.05) as well as incidence of liver metastasis (Gr. 4-6: 90.9% vs. 72.7% vs. 36.4%, P<0.05). Furthermore concentration of PGF(1)(alpha), PGE(2) and LT were significantly increased in pancreatic carcinoma compared to tumour-free tissue. Moreover levels of PGF(1)(alpha) and PGE(2) were higher in liver metastasis than in extrametastatic hepatic tissue. However, in Gr. 6 (FISH-OIL) intrametastatic concentration of LT was significantly lower than in non-metastatic hepatic tissue as well as in Gr. 4 and Gr. 5. FISH-OIL decreased number of visible pancreatic tumours and incidence of histological proven liver metastasis. This effect might be caused by a decrease of intrametastatic concentration of LT compared to extrametastatic hepatic tissue.     

Influence of conjugated vs. conventional linoleic acid on liver metastasis and hepatic lipidperoxidation in BOP-induced pancreatic cancer in Syrian hamster

While conjugated linoleic acid (CLA) is regarded as an essential fatty acid with anticarcinogenic effects, conventional linoleic acid (LA) is reported to promote tumour growth in various experimental studies probably caused by high sensitivity to non-enzymatic lipid peroxidation. In order to evaluate the impact of dietary LA and CLA on liver metastasis and lipidperoxidation (LPO), 60 Syrian hamsters were injected with 10 mg N -nitrosobis-2-oxopropylamine (BOP)/kg body weight s.c. for 12 weeks. Animals were fed a special diet containing LA or CLA. The experiment was terminated after 24 weeks. Incidence, number and size of liver metastases were histologically determined. Furthermore, the activities of antioxidative enzymes and concentration of hepatic lipidperoxidation were measured intra- and extrametastatically. Incidence, number and size of liver metastases did not differ between the tumour groups. Otherwise, antioxidative enzyme activity of GSH-Px was higher in non-metastatic liver, while SOD activity and lipidperoxidation were increased in liver metastases. Conclusively there was no difference between the groups fed with LA and CLA according to the impact on liver metastasis in ductal pancreatic cancer.     

Inhibitory effect of esculin on oxidative DNA damage and carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine in hamster pancreas

The effects of esculin, a natural coumarin compound, on the formation of 8-oxo-2'-deoxyguanosine (8-oxodG) and carcinogenesis induced by a chemical carcinogen, N-nitrosobis(2-oxopropyl)amine (BOP), were examined in the pancreas of female Syrian golden hamsters. Animals were given a diet containing esculin for 7 days, and killed 4~h after BOP treatment, and the contents of 8-oxodG were measured in the nuclear DNA of the pancreas. Esculin suppressed significantly the increase in the 8-oxodG content of hamster pancreas induced by BOP. Furthermore, the effect of esculin on the rapid production model experiment for pancreatic carcinogenesis using BOP was investigated. Esculin was given ad libitum as a 0.05% aqueous solution during either the initiation or promotion phases. The incidence of invasive tumors in animals given esculin during the initiation phase was significantly lower than in the control group, while the incidence in animals given esculin during the promotion phase showed no significant change. These results suggest that the intake of esculin has an inhibitory effect on BOP-induced oxidative DNA damage and carcinogenesis in hamster pancreas.     

Does enteral nutrition of dietary polyunsaturated fatty acids promote oxidative stress and tumour growth in ductal pancreatic cancer?: Experimental trial in Syrian Hamster

BACKGROUND: Type and composition of dietary fat intake is supposed to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 polyunsaturated fatty acids (PUFA) on oxidative stress (lipidperoxidation) and tumour growth in ductal pancreatic cancer. METHODS: Ninety male hamsters were randomized into 6 groups (gr.) (n=15) and allocated to 3 main dietary categories: gr. 1 and 2 received a standard high fat diet (SHF, rich in n-6 PUFA), while gr. 3 and 4 were fed with a diet containing a mixture of n-3, n-6 and n-9 PUFA (SMOF) and gr. 5 and 6 had free access to a diet rich in n-3 PUFA (FISH-OIL). Gr. 1, 3 and 5 received weekly subcutaneous (s.c.) injections of 10 mg N-nitrosobis-2-oxypropylamine (BOP)/kg body weight in order to induce ductal pancreatic adenocarcinoma. Healthy control gr. 2, 4 and 6 were treated with 0.5 ml 0.9% sodium chloride s.c. After 32 weeks all animals were sacrificed. Removed pancreata were weighed and analysed histologically and biochemically. Activities of glutathionperoxidase (GSH-Px), superoxiddismutase (SOD) and levels of lipidperoxidation were measured in samples of pancreatic carcinoma as well as in tumour-free pancreatic tissue. RESULTS: While different diets did not significantly alter the overall incidence of histologically proven pancreatic adenocarcinoma, the number of macroscopically visible tumours was decreased in the FISH-OIL-gr. CONCLUSION: Different diets did not significantly influence the incidence of histologically proven pancreatic adenocarcinoma. However, administration of a diet rich in n-3 PUFA (FISH-OIL) resulted in a decrease of macroscopically visible tumours, thus indicating its beneficial effects in respect to attenuation of tumour growth.     

Histone H3 mRNA in situ hybridization for identifying proliferating cells in human pancreas, with special reference to the ductal system

In general, the incidence of proliferating cells parallels that of carcinogenesis. We have investigated proliferating activity and phenotype expression in epithelial cells in normal tissue, mucinous metaplasia and ductal adenocarcinoma of the pancreas. Twenty-eight resected pancreases (15 cases of pancreatic ductal adenocarcinoma and 13 cases of other diseases) were examined. Formalin-fixed, paraffin-embedded tissue sections were examined for proliferating cell activity using histone H3 mRNA in situ hybridization and immunostaining for Ki-67. In the normal pancreas, the labelling indices for proliferating cells were low and no generating zone was found. The following progressive increase was found in the labelling indices: normal ductal epithelium < mucinous metaplasia without papillary hyperplasia < mucinous metaplasia with papillary hyperplasia < ductal carcinoma. In the pancreatic ductal adenocarcinomas, the S-phase fraction, as defined by the ratio H3-mRNA-labelling index/Ki-67-labelling index, increased as the degree of differentiation decreased. Mucinous metaplasia with papillary hyperplasia showed organoid differentiation toward pyloric mucosa. If used in combination with other proliferative markers on paraffin-embedded tissue sections, histone H3 mRNA in situ hybridization could open broader perspectives on the biology of cell proliferation in the pancreatic ductal system.     

Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: inhibition of matrix metalloproteinases in pancreatic cancer

BACKGROUND: Matrix metalloproteinases (MMP) are proteolytic enzymes which degrade the extracellular matrix and therefore play an important role in metastasis. However, the impact of MMP inhibitors (MMPI) on pancreatic cancer is still unclear. Thus we evaluated the influence of selective MMPI Ro 28-2653 on the incidence of liver metastases and the concentration of MMP-2 and MMP-9 in ductal pancreatic adenocarcinoma in Syrian hamster. MATERIAL AND METHODS: One hundred and thirty male Syrian hamsters were randomised into 8 groups (Gr.1-3: n=15, Gr.4-8: n=17). Pancreatic cancer was induced by weekly subcutaneous injection of 10mg N-nitrosobis-2-oxopropylamin (BOP)/kg body weight (Gr.4-8) while healthy control Gr. 1-3 received 0.5 ml sodium chloride 0.9%. Gr.1 and 4 had free access to a standard diet, Gr. 2, 3 and 5-8 received a diet rich in polyunsaturated fatty acids, which increases liver metastasis in this model. In week 17 oral therapy started: Gr.3 and 6: 60 mg Eudragit/kg body weight/d (vehicle of MMPI), Gr.7 and 8: 40 mg, respectively, 120 mg RO 28-2653/kg body weight/d; Gr.1, 2, 4, 5: no therapy. After 30 weeks all hamsters were sacrificed and histopathologically examined. Additionally concentrations of MMP-2 and MMP-9 were measured in non-metastatic liver and liver metastases. RESULTS: Concentrations of MMP-2 and MMP-9 in liver metastases were decreased by high- and low-dose therapy with MMPI. Furthermore, the incidence of liver metastases was significantly reduced by low-dose therapy with Ro 28-2653. CONCLUSION: Low-dose therapy with Ro 28-2653 decreased liver metastasis due to an inhibition of MMP-2 and MMP-9 concentration in ductal pancreatic cancer.     

Effect of green tea catechins on oxidative DNA damage of hamster pancreas and liver induced by N-Nitrosobis(2-oxopropyl)amine and/or oxidized soybean oil

It has been indicated that high fat diet is a risk factor of the pancreatic cancer by epidemiological studies. We examined whether the oxidized soybean oil (ox-oil) express the synergistic effect on the formation of 8-oxo-2'-deoxyguanosine (8-oxodG) in nuclear DNA of hamster pancreas induced by N-Nitrosobis(2-oxopropyl)amine (BOP) and whether the green tea catechins (GTC) suppressed it. Ox-oil was prepared by air oxidation, and the content of lipid hydroperoxide was 6.22 mg/ml. Hamsters were administered 0.3 ml of ox-oil/day orally for 4 weeks before BOP treatment. GTC was given ad libitum as a 0.1% aqueous solution. Four hours after subcutaneous administration of BOP, hamsters were sacrificed, and the contents of 8-oxodG were measured in nuclear DNA of pancreas and liver. The 8-oxodG content in the pancreas was increased by BOP and/or ox-oil administration. However, it was not suppressed by an intake of GTC. In the liver, though the content of 8-oxodG was increased by ox-oil, it tended to suppress the rise of 8-oxodG by a GTC intake. These results suggested that the long term intake of ox-oil might have the possibility to induce carcinogenesis in hamster pancreas and liver, and an intake of GTC might have the beneficial effect on liver.     

Suppression of 8-oxo-2'-deoxyguanosine formation and carcinogenesis induced by N-nitrosobis (2-oxopropyl)amine in hamsters by esculetin and esculin

Effects of esculetin (6,7-dihydroxycoumarin) and its glycoside, esculin, on 8-oxo-2'-deoxyguanosine (8-oxodG) formation and carcinogenesis induced by a chemical carcinogen, N-nitrosobis(2-oxopropyl)amine (BOP), were examined in the pancreas of female Syrian golden hamsters. Animals were administered esculetin by gastric intubation into the stomach 30 min before BOP administration or ingestion of a diet containing esculin for 7 days before BOP administration, and killed 1 or 4 h after BOP treatment, and the contents of thiobarbituric acid-reacting substrates (TBARS) and 8-oxodG in the pancreas were determined. Both compounds suppressed significantly the BOP-induced increases in 8-oxodG and TBARS contents in hamster pancreas. We further investigated the effect of esculin on pancreatic carcinogenesis by the rapid production model induced by augmentation pressure with a choline-deficient diet, ethionine, methionine and BOP. Esculin was given ad libitum as a 0.05% aqueous solution in either the initiation or promotion phases. The incidence of invasive tumors in animals given esculin during the initiation phase was significantly smaller than in the control group, while esculin given during the promotion phase showed no apparent effects. These results suggest that the intake of esculin has an inhibitory effect on BOP-induced oxidative DNA damage and carcinogenesis in hamster pancreas.     

Enhancement of the repair of carcinogen-induced DNA damage in the hamster pancreas by dietary selenium

We measured single strand breaks (SSB) in pancreas DNA produced by N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters fed purified diets containing added sodium selenite (Se) at 0.0, 0.1 and 5.0 ppm. There were fewer SSB in those given the 5.0 ppm Se diet throughout the experiment. One hour after dosing with BOP (20 mg/kg), there were 2.26 ± 0.47, 2.83 ± 0.43 and 1.74 ± 0.43 SSB per 10⁸ daltons (mean ± S.E.M.) respectively in the three groups. The SSB were repaired faster in the 5.0 ppm Se-fed group. The approximate half-lives of the SSB were 33, 30 and 8 days, respectively. In the hamsters fed 5.0 ppm Se there was a small, statistically significant increase in pancreatic DNA synthesis. Autoradiographic analysis indicated that this was repair synthesis. In a second experiment, hamsters were fed one of the three diets prior to and for 2 days after administration of a single dose of BOP (20 mg/kg). They were then fed the 5.0 ppm Se diet for 5 days. The number of SSB was compared with those in hamsters fed their original diet for 7 days after BOP dosing. There was a statistically significant difference in the number of SSB in the hamsters fed 0.1 ppm Se before and for 2 days after BOP. In these hamsters there were 1.21 ± 0.24 SSB per 10⁸ daltons compared with 3.19 ± 0.4 (mean ± S.E.M.). These results suggest high levels of dietary Se stimulate the repair of carcinogen-induced DNA damage.     

Suppression of 8-Oxo-2′-deoxyguanosine Formation and Carcinogenesis Induced by N-Nitrosobis(2-oxopropyl)amine in Hamsters by Esculetin and Esculin

Effects of esculetin (6,7-dihydroxycoumarin) and its glycoside, esculin, on 8-oxo-2′-deoxyguanosine (8-oxodG) formation and carcinogenesis induced by a chemical carcinogen, N-nitrosobis(2-oxopropyl)amine (BOP), were examined in the pancreas of female Syrian golden hamsters. Animals were administered esculetin by gastric intubation into the stomach 30?min before BOP administration or ingestion of a diet containing esculin for 7 days before BOP administration, and killed 1 or 4?h after BOP treatment, and the contents of thiobarbituric acid-reacting substrates (TBARS) and 8-oxodG in the pancreas were determined. Both compounds suppressed significantly the BOP-induced increases in 8-oxodG and TBARS contents in hamster pancreas. We further investigated the effect of esculin on pancreatic carcinogenesis by the rapid production model induced by augmentation pressure with a choline-deficient diet, ethionine, methionine and BOP. Esculin was given ad libitum as a 0.05% aqueous solution in either the initiation or promotion phases. The incidence of invasive tumors in animals given esculin during the initiation phase was significantly smaller than in the control group, while esculin given during the promotion phase showed no apparent effects. These results suggest that the intake of esculin has an inhibitory effect on BOP-induced oxidative DNA damage and carcinogenesis in hamster pancreas.     

Does a-linolenic acid in combination with linoleic acid influence liver metastasis and hepatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters?

Some fatty acids are reported to inhibit tumor growth of pancreatic carcinoma. However, it is still unknown if α-linolenic acid (ALA) and linoleic acid (LA) inhibit liver metastasis of ductal pancreatic adenocarcinoma. Therefore we studied the effect of these fatty acids on liver metastasis in the animal model of N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic adenocarcinoma in Syrian hamsters. Since lipid peroxidation seems to be involved in carcinogenesis and metastasis, we further analyzed the intrahepatic concentration of thiobarbituric acid-reactive substances (TBARS) and activity of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD).We observed an increase in the incidence and the number of liver metastase in response to the combination of ALA and LA. This was accompanied by a decrease in hepatic GSH-Px activity and an increase in hepatic SOD activity and TBARS concentration. The increase in hepatic lipid peroxidation seems to be one possible mechanism of increasing liver metastasis in this study.     

Does alpha-linolenic acid in combination with linoleic acid influence liver metastasis and hepatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters?

Some fatty acids are reported to inhibit tumor growth of pancreatic carcinoma. However, it is still unknown if alpha-linolenic acid (ALA) and linoleic acid (LA) inhibit liver metastasis of ductal pancreatic adenocarcinoma. Therefore we studied the effect of these fatty acids on liver metastasis in the animal model of N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic adenocarcinoma in Syrian hamsters. Since lipid peroxidation seems to be involved in carcinogenesis and metastasis, we further analyzed the intrahepatic concentration of thiobarbituric acid-reactive substances (TBARS) and activity of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD).We observed an increase in the incidence and the number of liver metastases in response to the combination of ALA and LA. This was accompanied by a decrease in hepatic GSH-Px activity and an increase in hepatic SOD activity and TBARS concentration. The increase in hepatic lipid peroxidation seems to be one possible mechanism of increasing liver metastasis in this study.     

Pancreatic exocrine damage induced by subcutaneous injection of a low dosage of zinc

The aim of this study was to observe whether a low dosage of zinc induced mouse pancreatic injury. Dosages of zinc from 0.1 to 50 mg/kg were injected subcutaneously in mice, and plasma and pancreatic clinical parameters were observed 3–24 h after the injection. Plasma α-amylase activity increased 10 and 24 h after the injection of 25 or 50 mg/kg of zinc, whereas pancreatic α-amylase activity decreased 3 h after more than 5 mg/kg of zinc was injected. The activity recovered after 24 h except in the group injected with 50 mg/kg of zinc. The plasma glucose level did not change when less than 25 mg/kg of zinc was injected. The pancreatic zinc contents increased 3 h after more than 1 mg/kg of zinc was injected. The pancreatic metallothionein (MT) contents increased 6 h after the injection of 1 mg/kg of zinc. In addition, when more than 5 mg/kg of zinc was injected, the MT content increased at 3 h. In histochemical observations, cell damages such as fibrosis and necrosis were observed in pancreatic exocrine cells, but not in cells of Langerhans islets. From the present study, a single injection of a low dosage of zinc induces injury in pancreatic exocrine cells, but not endocrine cells.     

Differences between pancreatropic nitrosamine carcinogens and N-nitrosodimethylamine in methylating DNA in various tissues of hamsters and rats

N-Nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxypropyl)amine (HPOP) induce pancreatic tumors in the Syrian hamster. BOP and HPOP target the kidneys, esophagus and upper respiratory system in rats, but the pancreas of this species is resistant to the above carcinogens. On the other hand, N-nitrosodimethylamine (DMN) induces hepatic and kidney tumors in the rat, and tumors of the liver and upper respiratory system in the hamster, but it is not known to affect the pancreas of either species. At equimolar doses, ratios of DMN versus BOP or HPOP mediated methylation in hamster liver DNA are 1.6 and 8.1, respectively. Respective ratios in the rat liver are 1.1 and 6.5. However, in both species equitoxic doses of BOP, HPOP and DMN induce similar levels of N7-methylguanine (N7-MeG) in hepatic DNA. At such doses methylation of kidney DNA is 24 and 14 times more extensive in BOP and HPOP than in DMN-treated hamsters. Similarly, ratios of N7-MeG in the pancreas of BOP and HPOP vs. DMN-treated hamsters are 10 and 5, respectively, while in the lung this ratio is 2.2 for both carcinogens. Levels of O6-methylguanine (O6-MeG) in the DNA of extrahepatic tissues are substantially greater in hamsters treated with BOP or HPOP than in those treated with an equitoxic dose of DMN. In rats, equitoxic doses of BOP and DMN induce similar levels of N7-MeG and O6-MeG in hepatic, kidney and lung DNA. However, levels of these adducts in pancreatic DNA are 2 times greater following BOP than DMN administration. Ratios of N7-MeG in pancreas, lung and kidney in HPOP vs. DMN-treated rats are 2.1, 2.7 and 2.1, respectively. Repair of O6-MeG is more effective in rat than in hamster liver, however in other tissues this is not always the case. Levels of O6-MeG in the pancreas of rats are reduced to half of their initial value between 40 and 50 h following the administration of 10, 50 or 20 mg/kg DMN, HPOP or BOP, respectively. However, half-lives for the repair of O6-MeG in hamster pancreas are 28, 62 and greater than 120 h at the respective doses of the above carcinogens. Since the above doses of DMN, HPOP and BOP induce 7, 19 and 41 nmol O6-MeG/mmol of guanine respectively in the hamster pancreas, it is suggested that the rate of repair could be a function of the initial concentration of this adduct. Differences between DMN and BOP or HPOP in methylating pancreatic DNA are sufficient to distinguish the latter two nitrosamines as pancreatic carcinogens for the hamster.     

Effects of selective COX-2 and 5-LOX inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster

Selective inhibition of eicosanoid synthesis seems to decrease carcinogenesis, however, the effect on liver metastasis in pancreatic cancer is still unknown. Ductal pancreatic adenocarcinoma was chemically induced by weekly injection of N-nitrosobis-2-oxopropylamine (BOP) in Syrian hamster. Animals received selective inhibition of cyclooxygenase-2 (Celebrex) and 5-lipoxygenase (Zyflo). In week 33, hamsters were sacrificed and incidence of pancreatic carcinomas as well as liver metastases were examined. Furthermore, size and number of liver metastases per animal were determined and concentration of PGF1alpha, PGE2 and leukotrienes was measured in hepatic and pancreatic tissue. Combined therapy (Celebrex+Zyflo) significantly decreased incidence, number and size of liver metastases. Furthermore extra- and intrametastatic concentration of PGE2 was reduced by this treatment in hepatic tissue. Single Cox-2-inhibition (Celebrex) decreased intrametastatic hepatic PGF1alpha and PGE2 concentration while PGF1alpha concentration was reduced in non-metastatic liver (nml). Moreover 5-LOX-inhibition (Zyflo) decreased intrametastatic PGE2 concentration as well as PGF1alpha and PGE2 in nml. In pancreatic carcinomas highest LT-concentration was found after combined treatment and this therapy group was the only one revealing a significantly higher amount of LTs in carcinomas compared to tumour-free tissue. Hepatic LT-concentration was significantly lower in the control groups than in nml of the tumour groups. Combination of Cox-2-inhibition and 5-Lox-inhibition might be a suitable adjuvant therapy to prevent liver metastasis in human ductal pancreatic adenocarcinoma.