Fischer 344 rats (60/sex/group) were given daily subcutaneous injections of recombinant human parathyroid hormone (PTH)(1-34) for 2 years at doses of 0, 5, 30, or 75 microg/kg. Treatment caused substantial increases in bone mass consistent with the known pharmacologic effects of once-daily administration. As determined by quantitative computed tomography (QCT) and histomorphometry, bone mass was markedly increased. Substantial new bone formation resulted in a large decrease in marrow space accompanied by altered bone architecture. Bone proliferative lesions were observed in all PTH( 1-34)-treated groups. Osteosarcoma occurred in 3, 21, and 31 male rats and in 4, 12, and 23 female rats in the 5-, 30-, and 75-microg/kg treatment groups, respectively. Focal osteoblast hyperplasia, osteoma, and osteoblastoma were much less frequent. Although the specific cellular or molecular mechanisms responsible for the rat bone tumors have not been fully elucidated, the data suggest that these lesions resulted from the long duration of treatment and the exaggerated pharmacologic response of the rat skeleton to daily treatment with PTH(1-34). Important differences between the rat study and clinical use in adult humans suggest that the increased incidence of bone neoplasia in rats treated for 2 years is likely not predictive of an increased risk of bone cancer in skeletally mature adult humans being given PTH(1-34) for a limited period of time in the treatment of osteoporosis.

Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety.

Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer.

https://www.gastrojournal.org/article/0016-5085(86)90938-8/pdf

Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation: Studies with omeprazole and ranitidine in intact and antrectomized rats

Small intramucosal tumours in the oxyntic area of the rat stomach were observed in an oncogenicity study with omeprazole. The tumours could be defined as carcinoids of enterochromaffin-like (ECL) cell origin. ECL cells occur exclusively in oxyntic mucosa and respond to the trophic hormone gastrin with a proliferation that becomes exaggerated in old rats. Inhibition of gastric acid secretion is known to induce hypergastrinaemia in rats. According to the common concept of endocrine cells, a sustained hormonal stimulation with gastrin may induce a continuous gradient between hyperplasia and neoplasia of the ECL cells. The tumours found are thus to be regarded as hormone-induced endocrine tumours of the ECL cells in the stomach. The ECL-cell tumours of the rats in the oncogenicity study appeared to belong to the low-malignancy type of carcinoids and did not make their appearance until the end-life period of the study. The sex and species differences observed may be explained by inherent differences in gastrin response, spontaneous ECL cell density or in responsiveness to gastrin-stimulated ECL cell proliferation between sexes and species.

Enterochromaffin-Like Cell Carcinoids of Gastric Mucosa in Rats after Life-Long Inhibition of Gastric Secretion

Incompletely processed gastrins have been postulated to play a role in growth of the gastrointestinal tract, but few studies have examined the effects of progastrin on mucosal proliferation in vivo. Human gastrin gene expression and progastrin processing were therefore studied in transgenic mice containing a human gastrin (hGAS) minigene, and compared to processing in mice bearing an insulin gastrin (INS-GAS) transgene that overexpresses amidated gastrin. Progastrin processing was studied using region-specific antisera and radioimmunoassays, biosynthetic labeling, immunoprecipitation, and HPLC. Proliferative effects due to overexpression of processed and unprocessed gastrin in INS-GAS and hGAS mice, respectively, were determined using routine histology and BrdU incorporation. The pancreatic islets of INS-GAS mice were able to produce carboxyamidated G-17, resulting in a twofold elevation of serum amidated gastrin, marked thickening of the oxyntic mucosa, and an increased BrdU labeling index (LI) of the gastric body. In contrast, livers of adult hGAS mice expressed abundant human gastrin mRNA and human progastrin but were unable to process this peptide to the mature amidated form, resulting in markedly elevated serum progastrin levels and normal amidated gastrin levels. Nevertheless, there was a marked increase in the BrdU labeling index of the colon in hGAS mice (LI 7.46+/-1.90%), as well as in INS-GAS mice (LI 6.16+/-1.17%), compared to age-matched, wild type control mice (LI 4.01+/-0.98%, P < 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo.

/pdf/processing-and-proliferative-effects-of-human-progastrin-in-3oh9m6zx5l.pdf

Processing and proliferative effects of human progastrin in transgenic mice.

As part of the safety evaluation of the gastric antisecretory drug, omeprazole, toxicological studies have been performed in several species of animals. The acute toxicity after oral administration to rodents was low. The oral LD50 value was above 4 g/kg. The general toxicity after repeated administration has been studied in rats and dogs. No clinical signs of adverse reactions were seen. Some minor changes in hematology parameters were observed. In rats and mice decreases in the erythrocyte count, hematocrit and hemoglobin have occasionally been found at doses of 125 mumol/kg/day and more. Hyperplasia of oxyntic mucosal cells, concomitant with increases in stomach weight, oxyntic mucosal thickness and folding, has been observed in the species investigated, the dog, rat and mouse. In addition, slight chief cell atrophy and eosinophilia of the chief cell granules were observed in rats. The oxyntic mucosal effects were reversible upon treatment being discontinued. In the oncogenicity studies, gastric carcinoids occurred in the rat but not in the mouse. Investigations of the carcinoids showed that the vast majority of the endocrine cells could be characterised as ECL-cells. The hyperplasia of oxyntic mucosal cells, including hyperplasia of endocrine ECL-cells and development of gastric carcinoids in rats, is attributable to the pronounced hypergastrinemia produced as a secondary effect of almost complete inhibition of acid secretion by the large doses of omeprazole used in the toxicity studies. In agreement with this hypothesis, the hyperplasia of the oxyntic cells was prevented by antrectomy. The reproduction studies performed in rats and rabbits showed no sign of fetal toxicity or teratogenic effect. The results of the short-term mutagenicity tests, Ames test, the micronucleus test in mice and the mouse lymphoma test were all negative.

C Lundberg

Papers

Toxicological studies on omeprazole.