yf-476 and Pancreatic-Neoplasms

Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCK

Topics: Animals; Antineoplastic Agents; Benzodiazepinones; Disease Models, Animal; Drug Design; Gastric Acid; Gastrins; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Phenylurea Compounds; Receptor, Cholecystokinin B; Stomach Neoplasms

The experience of synthesising a novel gastrin receptor antagonist gastrazole and taking it into 3 small clinical studies in pancreatic cancer in man is described. The need for such a compound is illustrated by the observation that inhibition of gastric acid secretion by H2 receptor antagonists results in hypergastrinaemia. A large number of cell types have gastrin receptors including pancreatic cancer cells which have been shown to be stimulated by gastrin. Small numbers of pancreatic cancer patients given gastrazole by continuous intravenous infusion showed prolonged survival compared with best supportive care or placebo, and equivalent survival to those given 5 fluouracil. The results suggest a greater benefit for patients with early stage disease. An alternative gastrin receptor antagonist YF 476 is also described which has the advantage of efficacy given by the oral route. This new compound requires to be studied in pancreatic cancer and other diseases associated with hypergastrinaemia.

Topics: Animals; Antineoplastic Agents; Benzodiazepinones; Clinical Trials as Topic; Cyanoacrylates; Drug Design; Fluorouracil; Gastric Acid; Gastrins; Humans; Infusions, Intravenous; Mice; Pancreatic Neoplasms; Phenylurea Compounds; Pilot Projects; Receptor, Cholecystokinin B; Receptors, Histamine H2; Xenograft Model Antitumor Assays

Gastrin signaling mediated through cholecystokinin-2 receptor (CCK2R) and its downstream molecules is altered in pancreatic cancer. CCK2R antagonists, YF476 (netazepide) and JNJ-26070109, were tested systematically for their effect on pancreatic intraepithelial neoplasia (PanIN) progression to pancreatic ductal adenocarcinoma (PDAC) in Kras

Topics: Adenocarcinoma; Animals; Benzodiazepinones; Carcinoma in Situ; Carcinoma, Pancreatic Ductal; Chemoprevention; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Proteins; Pancreatic Neoplasms; Phenylurea Compounds; Proto-Oncogene Proteins p21(ras); Quinoxalines; Receptor, Cholecystokinin B; Signal Transduction; Sulfonamides