Pre-clinical 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 factors for colorectal tumours. The immunogen Gastrimmune is composed of the amino terminus of gastrin-17 linked to diphtheria toxoid and raises antibodies in situ which neutralise amidated and glycine-extended gastrin-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 the rat colon tumour DHDK12. Gastrimmune was administered to rats s.c. at 3 weekly intervals. The rat colon tumour line DHDK12 was injected into the abdominal wall of BDIX rats. Combinations of 5-FU/leucovorin were injected i.v. on days 1, 3 and 5, with the cycle repeated every 4 weeks. Antibody titres were measured by an ELISA technique. Antibody titres were followed for 40 weeks after Gastrimmune (500 microg.ml(-1)) immunization, with titres peaking between 10 and 20 weeks after a single immunisation and falling by week 30. At termination, no effect was observed on either the histological appearance of the gastro-intestinal tract or the proliferation of the colonic mucosa. Pre- and post-treatment with 5-FU/leucovorin (30 mg.kg(-1)) had no effect on the kinetics and level of antibody response to Gastrimmune. Gastrimmune (200 microg.ml(-1)) and 5-FU/leucovorin combinations (12.5 and 20 mg.kg(-1)) increased 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 combination with 5-FU/leucovorin.
Watson
S A
SA
Department of Surgery, University Hospital, University of Nottingham, UK. Sue.Watson@nottingham.ac.uk
Michael
D
D
Justin
T A
TA
Grimes
S
S
Morris
T M
TM
Robinson
G
G
Clarke
P A
PA
Hardcastle
J D
JD
D000818:Animals; D000917:Antibody Formation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D019496:Cancer Vaccines; D015179:Colorectal Neoplasms / Q000628:therapy*; D004064:Digestive System / Q000473:pathology; D004168:Diphtheria Toxoid / Q000008:administration & dosage*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D005755:Gastrins / Q000008:administration & dosage*; D007115:Immunization Schedule; D007167:Immunotherapy; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D051381:Rats
D019496:Cancer Vaccines; D004168:Diphtheria Toxoid; D005755:Gastrins; C482698:gastrin immunogen; D002955:Leucovorin; D005472:Fluorouracil