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Abstract
YF476 is a potent and highly selective cholecystokin 2 (CCK(2)) receptor antagonist
of the benzodiazepine class. It inhibits gastric neuroendocrine enterochromaffin-like
(ECL) cell secretion, proliferation and spontaneous formation of gastric neuroendocrine
tumors (carcinoids) in cotton rats. The Mastomys rodent species exhibits a genetic
predisposition to gastric ECL neuroendocrine tumor formation which can be accelerated
by acid suppression and induction of hypergastrinemia. In this respect, it mimics
the human condition of atrophic gastritis, hypergastrinemia and gastric carcinoid
development. We investigated whether YF476 could inhibit acid suppression-induced
ECL cell hyperplasia and neoplasia in this model. In addition, we examined whether
YF476 could reverse established ECL cell hyperplasia and neoplasia. Targeting the
CCK(2) receptor during Loxtidine-induced hypergastrinemia resulted in a reduction
in ECL cell secretion (plasma and mucosal histamine, and histidine decarboxylase (HDC)
transcripts, p<0.05) and proliferation (numbers of HDC-positive cells, connective
tissue growth factor (CTGF) and cyclin D1 transcription). This was associated with
a decrease in ECL cell hyperplasia and a 60% reduction in gastric ECL cell microcarcinoid
(tumors <0.3mm in size) formation. YF476 inhibited ECL cell neoplasia (gastric carcinoid)
in animals with hyperplasia, inhibited the formation of ECL cell tumors when co-administered
with Loxtidine and reversed the growth and developement of gastric ECL cell carcinoids
in long-term acid suppressed Mastomys. Variable importance analysis using a logistic
multinomial regression model indicated the effects of YF476 were specific to the ECL
cell and alterations in ECL cell function reflected inhibition of transcripts for
HDC, Chromogranin A (CgA), CCK(2) and the autocrine growth factor, CTGF. We conclude
that specifically targeting the CCK(2) receptor inhibits gastrin-mediated ECL cell
secretion and ECL cell proliferation and tumor development in vivo.
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