Gastrin sensitivity of primary human colorectal cancer: the effect of gastrin receptor antagonism.
The purpose of this study was to determine the effect of the gastrin receptor antagonist, CR2093, on basal and gastrin-stimulated growth of primary human colorectal adenocarcinomas and to relate this to gastrin receptor expression. Tumour cells, derived from surgical specimens by enzymatic disaggregation, were grown on matrices of type I collagen and irradiated fibroblasts. Gastrin receptor expression was measured by using a mouse monoclonal antibody directed against the gastrin receptor and an avidin-biotin immunocytochemical method. Increased growth in the presence of gastrin-17 (used at physiological concentrations and as assessed by [3H] thymidine uptake) was shown in 16/34 (47%) tumours. CR2093 significantly reversed this stimulated growth (P < 0.05, one way analysis of variance) in 9/16 (56.3%) of the tumours and inhibited the basal growth of 11/34 (32.4%). Basal growth inhibition was reversed by gastrin-17 in 82% (9/11) of tumours. Gastrin receptor expression was widespread, but was not related to the degree of growth response to gastrin, and there was no significant correlation between intensity of receptor expression and inhibition of basal growth by CR2093. In conclusion, both gastrin-stimulated and basal growth of primary human colorectal can be inhibited by gastrin receptor antagonism, but gastrin receptor expression does not predict the sensitivity of tumours to (i) the proliferative effects of gastrin or (ii) the inhibitory effects of a gastrin receptor antagonist on basal growth. Antigastrin agents may have clinical value in the treatment of gastrin-sensitive colorectal tumours, and gastrin receptor expression may be related to endogenous gastrin production by colorectal tumour cells.
Watson
S A
SA
Department of Surgery, Queen's Medical Centre, Nottingham, U.K.
Clifford
T
T
Sykes
R E
RE
Robinson
E
E
Steele
R J
RJ
D000596:Amino Acids / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005755:Gastrins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000596:Amino Acids; D005755:Gastrins; D006727:Hormone Antagonists; D006728:Hormones; D011949:Receptors, Cholecystokinin; C075449:CR 2093; C013550:gastrin 17; D013936:Thymidine