Pinski J, Halmos G, Yano T, Szepeshazi K, Qin Y, Ertl T, Schally A V
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146.
Int J Cancer. 1994 May 15;57(4):574-80. doi: 10.1002/ijc.2910570422.
Nude mice bearing xenografts of the gastrin-responsive human gastric carcinoma MKN45 cell line were treated for 4 to 5 weeks with bombesin/gastrin-releasing-peptide(GRP) antagonist (RC-3095), somatostatin analogues 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 extent by RC-160 and SMS 201-995, administered by daily s.c. injections at a dose of 100 micrograms/day. Bombesin/GRP antagonist RC-3095, given s.c. at a dose of 20 micrograms/day, had the greatest inhibitory effect on tumor growth. The combination of RC-3095 with RC-160 did not further potentiate the suppression of tumor growth. Histologically, the number of mitotic cels decreased significantly in the groups treated with RC-160 or the combination of RC-3095 with RC-160. Serum gastrin levels were significantly diminished in all treated groups. Therapy with RC-160 or the combination also significantly decreased levels of serum growth hormone. Receptor assays on tumor membranes showed that bombesin was bound to 2 classes of receptor sites, one with high affinity and low capacity, the other with low affinity and high capacity. Binding sites for epidermal growth factor (EGF) were down-regulated in tumor cells after treatment with RC-3095, RC-160 or the combination of RC-3095 with RC-160. In studies in vitro, both RC-160 and RC-3095 significantly inhibited the proliferation of MKN45 cells in culture as measured by cell number. These data demonstrate, for the first time, that the growth of human gastric cancer in nude mice can be inhibited not only by somatostatin analogues, but also by administration of modern bombesin/GRP antagonists, such as RC-3095.
用蛙皮素/胃泌素释放肽（GRP）拮抗剂（RC - 3095）、生长抑素类似物RC - 160和SMS 201 - 995或RC - 3095与RC - 160的组合，对携带胃泌素反应性人胃癌MKN45细胞系异种移植瘤的裸鼠进行4至5周的治疗。通过每天皮下注射100微克/天的剂量给予RC - 160和SMS 201 - 995，肿瘤体积和重量显著降低至相似程度。以每天20微克/天的剂量皮下给予蛙皮素/GRP拮抗剂RC - 3095，对肿瘤生长具有最大的抑制作用。RC - 3095与RC - 160的组合并未进一步增强对肿瘤生长的抑制作用。组织学上，在接受RC - 160或RC - 3095与RC - 160组合治疗的组中，有丝分裂细胞数量显著减少。所有治疗组的血清胃泌素水平均显著降低。用RC - 160或该组合进行治疗也显著降低了血清生长激素水平。对肿瘤膜进行的受体分析表明，蛙皮素与两类受体位点结合，一类具有高亲和力和低容量，另一类具有低亲和力和高容量。在用RC - 3095、RC - 160或RC - 3095与RC - 160的组合治疗后，肿瘤细胞中表皮生长因子（EGF）的结合位点下调。在体外研究中，通过细胞数量测量，RC - 160和RC - 3095均显著抑制培养的MKN45细胞的增殖。这些数据首次证明，裸鼠体内人胃癌的生长不仅可以被生长抑素类似物抑制，还可以通过给予现代蛙皮素/GRP拮抗剂（如RC - 3095）来抑制。
