Antibodies raised by gastrimmune inhibit the spontaneous metastasis of a human colorectal tumour, AP5LV.
Both precursor forms of gastrin and mature amidated gastrin peptides can enhance proliferation of colorectal tumours and may regulate growth in an autocrine manner. The purpose of this study was to evaluate the effect of neutralization of precursor and amidated gastrin on primary and secondary in vivo growth of a human colorectal tumour. The human colorectal cell line, AP5LV, when injected into the muscle layer of the abdominal wall of severe combined immunodeficient (SCID) mice, grows as a well-vascularized primary tumour and metastasis to the lung. AP5LV expressed the precursor gastrin forms; progastrin and glycine-extended gastrin and gastrin/CCKB receptors, as assessed by immunocytochemistry. Gastrimmune is a gastrin immunogen in which the amino terminus of the gastrin-17 molecule is linked to diphtheria toxoid and induces antibodies which neutralise the amidated and glycine-extended forms of gastrin-17. Rabbit antiserum, raised against Gastrimmune, was administered intravenously into SCID mice bearing AP5LV tumours. Control animals were treated with antiserum raised against diphtheria toxoid only. Antibodies raised against Gastrimmune significantly limited the growth of primary AP5LV tumours, as assessed by median cross-sectional area (controls = 244 mm2; antibody-treated = 179 mm2; P = 0.033). In addition Gastrimmune-induced antiserum limited the growth of lung metastasis as assessed by nodule number (controls = 3.5; antibody-treated = 1.0; P = 0.0001) and nodule cross-sectional as assessed by image analysis (controls = 11.9 mm2; antibody-treated = 3.75 mm2; P = 0.0064). In conclusion in vivo neutralization of gastrin forms, which may potentially be fueling growth by an autocrine pathway, inhibited both primary growth and, to a greater degree, lung metastasis of a human colorectal tumour cell line. Immunization against tumour-associated gastrin forms may provide an effective therapy for advanced colorectal cancer.
Watson
S A
SA
Department of Surgery, University Hospital, Nottingham, U.K. sue.watson@nottingham
Michaeli
D
D
Morris
T M
TM
Clarke
P
P
Varro
A
A
Griffin
N
N
Smith
A
A
Justin
T
T
Hardcastle
J D
JD
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000627:therapeutic use*; D019496:Cancer Vaccines; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004168:Diphtheria Toxoid / Q000276:immunology / Q000627:therapeutic use*; D005755:Gastrins / Q000276:immunology* / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D011817:Rabbits; D051381:Rats; D014407:Tumor Cells, Cultured
D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D004168:Diphtheria Toxoid; D005755:Gastrins; C482698:gastrin immunogen