INHIBITION OF GROWTH OF MKN45 HUMAN GASTRIC-CARCINOMA XENOGRAFTS IN NUDE-MICE BY TREATMENT WITH BOMBESIN GASTRIN-RELEASING-PEPTIDE ANTAGONIST (RC-3095) AND SOMATOSTATIN ANALOG RC-160

Nude mice bearing xenografts of the gastrin-responsive human gastric c arcinoma MKN45 cell line were treated for 4 to 5 weeks with bombesin/g astrin-releasing-peptide(GRP) antagonist (RC-3095), somatostatin analo gues RC-160 and SMS 201-995, or the combination of RC-3095 and RC-160. Tumor volumes and weights were reduced significantly to a similar ext ent by RC-160 and SMA 201-995, administered by daily s.c. injections a t a dose of 100 mu g/day. Bombesin/GRP antagonist RC-3095, given s.c. at a dose of 20 mu g/day, had the greatest inhibitory effect on tumor growth. The combination of RC-3095 with RC-160 did not further potenti ate the suppression of tumor growth. Histologically, the number of mit otic cells decreased significantly in the groups treated with RC-160 o r the combination of RC-3095 with RC-160. Serum gastrin levels were si gnificantly diminished in all treated groups. Therapy with RC-160 or t he combination also significantly decreased levels of serum growth hor mone. Receptor assays on tumor membranes showed that bombesin was boun d to 2 classes of receptor sites, one with high affinity and low capac ity, the other with low affinity and high capacity. Binding sites for epidermal growth factor (EGF) were down-regulated in tumor cells after treatment wit RC-3095, RC-160 or the combination of RC-3095 with RC-1 60. In studies in vitro, both RC-160 and RC-3095 significantly inhibit ed the proliferation of MKN45 cells in culture as measured by cell num ber. These data demonstrate, for the first time, that the growth of hu man gastric cancer in nude mice can be inhibited not only by somatosta tin analogues, but also by administration of modern bombesin/GRP antag onists, such as RC-3095. (C) 1994 Wiley-Liss, Inc.