Katherine Kazakoff

The intracellular mechanism of insulin resistance in the hamster pancreatic ductal adenocarcinoma model.

Diabetes associated with pancreatic cancer is characterized by profound peripheral insulin resistance. The intracellular mechanism of insulin resistance was investigated in skeletal muscles from. N-nitrusobis(2-oxopropy1)(BOP)-treated hamsters. Effects of high-fat diet and exercise also were studied. BOP (20 mgkg body weight) was administrated weekly for 2 weeks. Hyperinsulinemia was found in BOP-treated hamsters at 20 weeks after BOP treatment, suggesting the peripheral insulin resistance is an early feature in pancreatic cancer. Hamsters were killed at 42 weeks, and soleus muscles were taken for the analysis. Skeletal muscle insulin-receptor binding and insulin receptor tyrosine kinase activities were similar between the control and BOP-treated hamsters. However, maximal muscle glycogen synthase activity was significantly reduced in BOP-treated hamsters compared with the control group. Muscle glycogen phosphorylase activity was increased in the BOP-treated group fed with high-fat diet as well as in BOP-treated groups with exercise. These findings indicate that insulin resistance in the hamster pancreatic cancer model is caused by a postreceptor defect, which led to significant decrease of muscle glycogen synthase activity. Whereas a high-fat diet causes more severe insulin resistance in BOPtreated hamsters, high-fat diet and exercising had no significant effects on skeletal muscle insulin-receptor function and glycogen synthase activity. Furthermore, both high-fat diet and exercise enhanced glycogen phosphorylase activity in BOPtreated hamsters.

The patterns of coexpression of tumor-associated antigens CA 19-9, TAG-72, and DU-PAN-2 in human pancreatic cancer

SummaryCoexpression of CA 19-9, DU-PAN-2, and TAG-72 was examined by a multilabeling immunohistochemical procedure in 31 surgically resected human pancreatic carcinomas. CA 19-9 was expressed in 74%, DU-PAN-2 in 84%, and TAG-72 in 65% of the cases. CA 19-9 and DU-PAN-2 were coexpressed in 16 cases (52%), CA 19-9 and TAG-72 in 10 cases (32%), DU-PAN-2 and TAG-72 in 8 cases (26%), and all three antigens in 10 tumors (32%). With the combination of the three antibodies, all 31 tumors were labeled. However, heterogeneity in antigen expression existed and the antibodies against CA 19-9, DU-PAN-2, and TAG-72 depicted 55%, 49%, and 35% of the tumor cells, respectively. The average number of cells coexpressing CA 19-9 and DU-PAN-2, CA 19-9 and TAG-72, DU-PAN-2, and TAG-72 was 22%, 11%, and 10%, respectively. Only about 3% of tumor cells coexpressed all three antigens, whereas 8% of tumor cells did not express any of the antigens. There was no correlation between the patterns of antigen expression and age or sex. However, there was a tendency of reduced CA 19-9, DU-PAN-2, and TAG-72 expression in less differentiated tumor areas. The results show that: 1) pancreatic cancer cells coexpress two or three antigens in different proportions; and 2) although the sensitivity for pancreatic cancer reaches 100% by all three antibodies, a remarkable heterogeneity exists and a minor fraction of tumor cells does not seem to produce any of these antigens.

Effects of raw soya diet and cholecystokinin receptor blockade on pancreatic growth and tumor initiation in the hamster

Raw soya diet in the hamster had short-term trophic effects on the pancreas, causing significant increases in pancreatic weight, DNA, RNA, and protein. These changes appear to be mediated by cholecystokinin (CCK) because the increases were blocked by infusion of the CCKA receptor antagonist, MK329. Raw soya diet significantly increased plasma levels of CCK in both the short-term and long-term studies. However, raw soya did not potentiate pancreatic cancer in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Infusion of MK329 during the initiation period of carcinogenesis did not change tumor incidence or yield, suggesting that endogenous CCK does not influence tumor induction during the initiation period in the hamster.

Involvement of cytochrome P450 2E1-like isoform in the activation of N-nitrosobis(2-oxopropyl)amine in the rat nasal mucosa

Induction of tumours in the nasal olfactory region of MRC rats by N-nitrosobis(2-oxopropyl)amine (BOP) is inhibited by orchiectomy and restored by testosterone. These results suggest the involvement of a sex-specific enzyme in BOP bioactivation in rat nasal mucosa. The present study was undertaken to identify this enzyme. Enzyme-linked immunosorbent assay (ELISA) and the metabolism of known substrates (p-nitrophenol) pointed to a microsomal cytochrome P450 (P450) 2E1-like isoform as a candidate enzyme. A correlation was found between the enzyme activity in nasal mucosal microsomes and serum testosterone levels. Four times more activity was detected in the nasal mucosa than in the liver of male rats. Vanillin inhibited the activity of the nasal mucosal enzyme to a greater extent than that of the liver enzyme. The overall results suggest that a nasal mucosal P450 2E1-like isoform is involved in BOP metabolism.

Effect of secretin on pancreatic carcinogenesis in the hamster model

Secretin (SEC) given s.c. to hamsters at a dose of 100 clinical units/kg body weight by 6 injections each 30 min apart, inhibited induction of pancreatic cancer when it was given prior to or simultaneously with a single dose of N-nitrosobis(2-oxopropyl)amine (BOP), but was ineffective in modifying tumor incidence when it was administered after BOP. The incidence of gall bladder and common bile tumors were not influenced, regardless of the time of SEC injections, implying that the inhibitory effect of this secretagogue is pancreas specific. However, a treatment schedule in which BOP and SEC were given weekly for 20 weeks did not alter the incidence of pancreatic tumors.