Gastric Neuroendocrine Tumors With Parietal Cell Atrophy in a Long-term Carcinogenicity Study in Rats.
Norimitsu Shirai1, Shambhunath Choudhary2, Christopher Houle1
1Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut, USA.
Toxicologic Pathology
|May 5, 2022
Summary
High doses of a novel cannabinoid-1 antagonist induced stomach neuroendocrine tumors in rats. This was linked to parietal cell atrophy and altered gastric acid secretion, a rare occurrence in rats.
Area of Science:
- Toxicology
- Gastroenterology
- Oncology
Background:
- Malignant neuroendocrine tumors are rare in rats.
- Cannabinoid-1 antagonists are novel therapeutic agents.
- Gastric mucosal changes can lead to tumor development.
Purpose of the Study:
- To investigate the potential carcinogenicity of a novel cannabinoid-1 antagonist.
- To evaluate the effects of the antagonist on gastric mucosa in Sprague-Dawley rats.
Main Methods:
- Female Sprague-Dawley rats were administered a high dose of a novel cannabinoid-1 antagonist for 89 weeks.
- Tumor incidence, gastric mucosal histology (parietal cell atrophy, foveolar hyperplasia), and potential mechanisms were assessed.
Main Results:
- Two out of sixty rats developed malignant neuroendocrine tumors in the stomach.
- Tumors were associated with significant parietal cell atrophy and foveolar hyperplasia.
- These gastric changes were considered test article-related at high doses.
Conclusions:
- The novel cannabinoid-1 antagonist may induce gastric neuroendocrine tumors in rats.
- Parietal cell atrophy, leading to altered gastric acid and gastrin feedback, is a potential mechanism.
- Further investigation is needed to understand the precise mechanism and long-term implications.
Keywords:
cannabinoid-1 antagonistfoveolar hyperplasiagastric carcinoidneuroendocrine tumorparietal cell atrophystomachMore Related Videos
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