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 ranter; thus, cholecystokinin (CCK) B/gastrin receptors may also be u p-regulated, A liver-invasive model of colon cancer was established with th e human colonic cell line C170HM2, which expresses the CCKB/gastrin recepto r 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 toroid. The peptide was denoted gastrin rec eptor protein (GRP) 1, The therapeutic effect of GRP1 antiserum was evaluat ed on the liver invasion of C170HM2 tumors, Biodistribution studies reveale d 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 tum or weight when compared with treatment with control serum in mice with an i ncreasing 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 a poptosis were increased in the GRP1 antiserum-treated tumors when compared with control serum-treated tumors. As shown by Western blotting, CCKB/gastr in receptor expression of C170HM2 xenografts after treatment with GRP1 anti serum shifted to a predominantly lower molecular weight form (M-r 45,000) t hat is known to be an internalized form of the receptor. In conclusion, tar geting of the CCKB/gastrin receptor may yield a valuable therapeutic modali ty for the treatment of advanced colon cancer.