Reflections on some pilot trials of gastrin receptor blockade in pancreatic cancer.
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.
Black
James W
JW
King's College London, School of Medicine, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. James.black@kcl.ac.uk
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001570:Benzodiazepinones / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003487:Cyanoacrylates / Q000627:therapeutic use; D015195:Drug Design; D005472:Fluorouracil / Q000627:therapeutic use; D005744:Gastric Acid / Q000378:metabolism; D005755:Gastrins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D007262:Infusions, Intravenous; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000627:therapeutic use; D010865:Pilot Projects; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D003487:Cyanoacrylates; D005755:Gastrins; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011970:Receptors, Histamine H2; C029868:Gastrozol; C104428:YF 476; D005472:Fluorouracil