PRECLINICAL EVALUATION OF THE GASTRIMMUNE IMMUNOGEN ALONE AND IN COMBINATION WITH 5-FLUOROURACIL LEUCOVORIN IN A RAT COLORECTAL-CANCER MODEL/

Mature and post-translational precursor gastrin forms are growth facto rs for colorectal tumours, The immunogen Gastrimmune is composed of th e amino terminus of gastrin-17 linked to diphtheria toroid and raises antibodies in situ which neutralise amidated and glycine-extended gast rin-17. The aim of the study was to determine the effect of treatment with 5-fluorouracil(5-FU)/leucovorin on the antibody titres induced by Gastrimmune and the effect of combination therapy on the growth of th e rat colon tumour DHDK12. Gastrimmune was administered to rats s.c. a t 3 weekly intervals, The rat colon tumour line DHDK12 was injected in to the abdominal wall of BDIX rats, Combinations of 5-FU/leucovorin we re injected i.v, on days 1, 3 and 5, with the cycle repeated every 4 w eeks, Antibody titres were measured by an ELISA technique. Antibody ti tres were followed for 40 weeks after Gastrimmune (500 mu g.ml(-1)) im munization, with titres peaking between 10 and 20 weeks after a single immunisation and falling by week 30, At termination, no effect was ob served on either the histological appearance of the gastro-intestinal tract or the proliferation of the colonic mucosa, Pre-and post-treatme nt with 5-FU/leucovorin (30 mg.kg(-1)) had no effect on the kinetics a nd level of antibody response to Gastrimmune. Gastrimmune (200 mu g.ml (-1)) and 5-FU/leucovorin combinations (12.5 and 20 mg.kg(-1)) increas ed the therapeutic effects on the in vivo growth of DHDK12 tumors when compared to the agents given singly. Gastrimmune immunisation may be a therapeutic option for the treatment of colorectal cancer in combina tion with 5-FU/leucovorin. (C) 1998 Wiley-Liss, Inc.