A comparison of an anti-gastrin antibody and cytotoxic drugs in the therapy of human gastric ascites in SCID mice.
The therapeutic effect of antibodies raised by the immunogen Gastrimmune was compared with both a CCKB/gastrin receptor antagonist, CI-988, and 5-Fluorouracil/leucovorin in a gastric cancer model. The human gastric ascites cell line, MGLVA1asc, produced and secreted progastrin and glycine-extended gastrin as determined by radioimmunoassay and immunocytochemistry. Cells were also stained with an antiserum directed against the human CCKB/gastrin receptor. MGLVAI asc cells were injected i.p. into SCID mice. Antibodies raised by Gastrimmune immunization of rabbits (affinity for G17 of 0.15 nM and GlyG17 of 0.47 nM) were passively infused i.p. and significantly enhanced survival by up to 5 days (p=0.0024 from vehicle controls). The enhancement in survival was not significantly different from that achieved by treatment with 5-Fluorouracil and leucovorin. A CCKB/gastrin receptor antagonist, CI-988, did not affect survival with cells injected at 7.5 x 10(5) cells/mouse but significantly increased the survival of mice injected with a lower cell innoculum of 5 x 10(5) cells/mouse from 30 to 35 days (p=0.0186). At this lower innoculum antibodies raised by Gastrimmune induced complete survival in 2 animals with the remaining dead by day 36 (p=0.0022). Thus, both endocrine and autocrine pathways mediated by precursor and mature gastrin molecules may be jointly operational in the gastric cancer scenario and may be important targets for therapeutic agents.
Watson
S A
SA
Department of Surgery, University of Nottingham, UK. sue.watson@nottingham.ac.uk
Michaeli
D
D
Grimes
S
S
Morris
T M
TM
Varro
A
A
Clarke
P A
PA
Smith
A M
AM
Justin
T A
TA
Hardcastle
J D
JD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001201:Ascites / Q000209:etiology / Q000628:therapy*; D019496:Cancer Vaccines; D004168:Diphtheria Toxoid / Q000276:immunology*; D005472:Fluorouracil / Q000008:administration & dosage; D005755:Gastrins / Q000276:immunology*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D016513:Mice, SCID; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D013274:Stomach Neoplasms / Q000150:complications / Q000628:therapy; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D004168:Diphtheria Toxoid; D005755:Gastrins; C482698:gastrin immunogen; D002955:Leucovorin; D005472:Fluorouracil