R. D. Beauchamp

Proglumide, a gastrin receptor antagonist, inhibits growth of colon cancer and enhances survival in mice.

Some tumors are responsive to hormone manipulation. Some gastric and colonic adenocarcinomas from both humans and animals have specific gastrin receptors. A transplantable mouse colon adenocarcinoma cell line (MC-26) contains gastrin receptors; growth of MC-26 colon cancer in vivo is stimulated by pentagastrin (PG). The purpose of this study was to determine whether a gastrin-receptor antagonist, proglumide (PGL), would inhibit growth of MC-26 colon cancer and prolong survival in tumor-bearing mice. Subcutaneous tumors were induced by injecting single-cell suspensions of MC-26 cells into 50 mice divided into 10/group. In Experiment 1, all mice received 1 X 10(5) tumor cells and treatment groups were divided as follows: Group A received intraperitoneal (IP) saline (0.2 ml tid beginning on day 1); B, IP, PGL (250 mg/kg tid) from day of tumor cell inoculation; and C, IP PGL (250 mg/kg tid) from day 7 after tumor implantation. In Experiment 2, mice were inoculated with half the number of tumor cells. Group I mice received saline and Group II received PGL in the same manner starting on day 1. Tumors were measured and all mice were sacrificed on day 23. In Experiment 1, mean tumor area in Group B (PGL-treated) was significantly smaller than Group A on days 11, 14, 17, and 21. Tumors of Group C were significantly smaller than controls on day 21. Survival of PGL-treated mice was significantly prolonged. In Experiment 2, mean tumor area, mean tumor weight, and tumor DNA and RNA content were significantly less in the PGL-treated group than control. It was concluded that growth of a gastrin-responsive colon cancer was inhibited and host survival was enhanced by treatment with a gastrin-receptor antagonist. Hormone manipulation may be a useful treatment for gastrointestinal cancers.

Lovastatin inhibits pancreatic cancer growth regardless of RAS mutation

Lovastatin, an inhibitor of the rate-limiting enzyme of cholesterol synthesis, inhibits growth of pancreatic cancer cells. A possible mechanism of this inhibition is that lovastatin inhibits the activity of RAS protein by depleting farnesyl (an intermediate of cholesterol synthesis). The K-ras gene is frequently mutated in pancreatic cancers and RAS protein requires farnesyl to be bound to the cell membrane and thereby activated. To investigate whether lovastatin inhibition of cell growth depends upon the presence of ras mutation, codons 12/13 and 61 of ras genes were examined by the dideoxynucleotide chain-terminating method in five pancreatic cell lines (human CAPAN2, CAV, MIA Paca2, PANC1, and hamster H2T) on which lovastatin exerted a growth-inhibitory effect. These codons play a major role in tumorigenic mutation of ras genes. Lovastatin inhibited cell growth by 99% (MIA), 97% (H2T), 78% (CAV), 41% (CAPAN2), and 23% (PANCI), respectively, when cells were treated with 2.5 μg/ml lovastatin for 6 days. Activating point mutations were found in codon 12 of the K-ras gene (wild type:GGT) in MIA (GTT), H2T (GAT), CAPAN2 (TGT), and PANCl (GAT) but not in CAV. In addition, the CAV cell line did not have a mutation in either H- or N-ras genes. Lovastatin inhibited the growth of CAV cells even though this cell line did not have ras mutation, suggesting that lovastatin inhibition of pancreatic cancer cell growth is not directly dependent on the presence of ras mutation.

Diagnostic role of gastrointestinal hormones in patients with chronic pancreatitis.

Thirty-three patients with chronic pancreatitis were studied in an effort to correlate release of gastrointestinal hormones (GIH) with the degree of pancreatic insufficiency. A prospective examination was conducted of fat-stimulated release of pancreatic polypeptide (PP), cholecystokinin (CCK), and neurotcnsin. Seventy-two-hour fecal fat determination, endoscopic retrograde pancreatography (ERP), and the bentiromide-PABA test were used to correlate the clinical stage of disease. The ERP was classified as positive only if the changes were advanced (or “marked”) according to the Cambridge Classification. Five patients were defined to have mild disease, 13 moderate, and 15 severe. Any patient with clinical evidence of chronic pancreatitis and ERP changes that were less than advanced and had normal fecal fat and bentiromide tests received a grade of mild. Patients with one abnormal test were graded moderate, and those with two or three abnormal results were graded severe. In the 33 patients, the integrated 60-minute release of pancreatic polypeptide (PP) was 37.4 ± 6.1 ng-60 min/ml in those five patients with mild disease, 102.3 ± 10.3 ng-60 min/ml in the 13 patients with moderate disease, and 7.6 ± 2.2 ng-60 min/ml in the 15 patients with severe disease. The integrated 60-minute release of neurotensin was 3.8 ± 0.4 ng-60 min/ml in mild disease, 2.0 ± 0.3 ng-60 min/ml in moderate disease, and 0.2 ± 0.1 ng-60 min/ml in severe disease. CCK release did not correlate with the severity of disease. Enhanced release of PP appeared to correlate well with moderate stage of chronic pancreatitis, and depressed PP release with severe disease. Stimulated levels of PP and neurotensin appear to be useful in the diagnosis and staging of chronic pancreatitis. It is concluded that measurement of fat-stimulated release of PP and neurotensin may be useful to assess severity of disease in patients with chronic pancreatitis.

Mechanisms of bombesin on growth of gastrinoma (PT) in vivo

The growth of the human gastrinoma model (PT) in athymic nude mice is stimulated by bombesin (BBS), an amphibian peptide homologous to both human gastrin-releasing peptide (GRP) and neuromedin B (NMB). The mechanism is not known, and a potent and specific GRP-R antagonist BIM26226, which has low affinity for NMB-R, was usedin vivo in athymic nude mice bearing gastrinoma subcutaneously. Both the BBS and BIM26226 stimulated the growth of PT, and the growth stimulation was even greater when given together. RT-PCR study of gastrinoma revealed the presence of both GRP-R and NMB-R mRNA, but much more abundant NMB-R mRNA. We conclude that BBS-stimulated growth of gastrinoma involves both GRP-R and NMB-R, and our findings suggest that GRP-R mediates negative and NMB-R produces positive growth effects on gastrinoma.

A high pressure liquid chromatography-radioimmunoassay method for measurement of cholecystokinin-8 and cholecystokinin-33/39 in plasma

Abstract A new high pressure liquid chromatography-radioimmunoassay method is described for the measurement of cholecystokinin-8 (CCK-8) and CCK-33/39 in plasma. The plasma levels of CCK-8-sulfate, CCK-8-desulfate, and CCK-33/39 were measured during the infusion of intraduodenal fat.

Systemic alterations in ornithine decarboxylase activity caused by colon cancer in mice

Tumors are known to cause profound changes in host biology, but the mechanisms responsible for these changes remain unclear. Ornithine decarboxylase (ODC) is a rate-limiting enzyme that catalyzes the biosynthesis of polyamines. The purpose of this study was to examine the effects of MC-26 tumor burden on ODC activity in the gastrointestinal tract, kidney and liver of mice. Forty-four Balb/c mice were randomly divided into 2 groups and the test group was pair-fed (to control). Group 1 was the tumor-free control. Group 2 was inoculated subcutaneously with 5 x 10(5) MC-26 cells. The ODC activity in the kidney and liver of tumor-bearing mice was significantly lower compared to tumor-free controls at sacrifice. ODC activity in the colon increased almost 4-fold. These results suggest that the presence of MC-26 tumor causes systemic effects that alter ODC activity. The tumor may elaborate a substance that suppresses ODC activity in some normal tissues while stimulating ODC activity in the tissue from which the tumor was derived.