Antiserum raised against an epitope of the cholecystokinin B/gastrin receptor inhibits hepatic invasion of a human colon tumor.
Serum gastrin is known to be elevated in patients with liver-metastasizing colon cancer; thus, cholecystokinin (CCK) B/gastrin receptors may also be up-regulated. A liver-invasive model of colon cancer was established with the human colonic cell line C170HM2, which expresses the CCKB/gastrin receptor at both the gene and protein level. An antiserum has been derived that is directed against the NH2-terminal 17 amino acids of the human CCKB/gastrin receptor coupled to diphtheria toxoid. The peptide was denoted gastrin receptor protein (GRP) 1. The therapeutic effect of GRP1 antiserum was evaluated on the liver invasion of C170HM2 tumors. Biodistribution studies revealed that GRP1 antiserum localized preferentially within the liver tumors when compared with normal liver tissue (1.5-fold increase after 24 h; P < 0.05). Antiserum against GRP1 inhibited both tumor take rate and final liver tumor weight when compared with treatment with control serum in mice with an increasing tumor burden. Liver tumor weights were reduced from 0.37 to 0.10 gram (P = 0.0155), 1.25 grams to 0.76 gram (P = 0.003) and 1.89 grams to 0.76 gram (P = 0.0068, all Mann-Whitney nonparametric U test). Necrosis and apoptosis were increased in the GRP1 antiserum-treated tumors when compared with control serum-treated tumors. As shown by Western blotting, CCKB/gastrin receptor expression of C170HM2 xenografts after treatment with GRP1 antiserum shifted to a predominantly lower molecular weight form (Mr 45,000) that is known to be an internalized form of the receptor. In conclusion, targeting of the CCKB/gastrin receptor may yield a valuable therapeutic modality for the treatment of advanced colon cancer.
Watson
S A
SA
Academic Unit of Cancer Studies, Queen's Medical Centre, University of Nottingham, United Kingdom. sue.watson@nottingham.ac.uk
Clarke
P A
PA
Morris
T M
TM
Caplin
M E
ME
D000595:Amino Acid Sequence; D000818:Animals; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000276:immunology / Q000378:metabolism; D007116:Immunization, Passive; D000922:Immunotoxins / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000276:immunology*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000939:Epitopes; D007106:Immune Sera; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin