Szepeshazi K, Schally A, Cai R, Halmos G, Groot K
VET AFFAIRS MED CTR,ENDOCRINE POLYPEPTIDE & CANC INST,NEW ORLEANS,LA 70146. TULANE UNIV,SCH MED,SECT EXPT MED,DEPT MED,NEW ORLEANS,LA 70146.
Int J Oncol. 1996 Sep;9(3):397-403. doi: 10.3892/ijo.9.3.397.
In three experiments, hamsters with N-nitroso-bis(2-oxopropyl)amine-induced pancreatic cancers were treated for two months with bombesin/GRP antagonists RC-3095 [D-Tpi(6),Leu(13)psi(CH2NH)Leu(14)-bombesin(6-14)], RC-3910-II [D-Tpi(6),Leu(13)psi(CH2N)Tac(14)-bombesin(6-14)], RC-3940-II [Hca(6),Leu(13)psi(CH2N)Tac(14)-bombesin(6-14)], RC-3950-II [D-Phe(6),Leu(13)psi(CH2N)Tac(14)-bombesin(6-14)], somatostatin analog RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2), or the combination of RC-3095 with RC160. All peptides inhibited pancreatic cancers to various degrees, reducing the number of tumorous animals, lowering the weight of tumorous pancreata by 40-55% and decreasing AgNOR numbers which are indicators of cell proliferation rate. Combination therapy with RC-3095 and RC-160 did not inhibit tumors better than single peptides. Among new bombesin/GRP antagonists, RC-3940-II had the strongest inhibitory effect. RC-3950-II and RC-3095 caused similar inhibition, but RC-3910-II was less effective. Tumor inhibitory activity of the bombesin/GRP antagonists was correlated with their binding affinities to bombesin receptors on tumor cells. RC-3940-II caused 50% inhibition of specific binding of [I-125-Tyr(4)]bombesin to tumor cell membranes at 0.96 nM concentration, while the IC50 for RC-3950-II was 5.27 nM and 12.94 nM for RC-3095. Our findings suggest that in addition to RC-3095, other bombesin/GRP antagonists such as RC-3950-II and especially RC-3940-II could be further developed for therapy of human pancreatic cancer.
在三项实验中，用N-亚硝基双（2-氧代丙基）胺诱导患胰腺癌的仓鼠，用蛙皮素/胃泌素释放肽拮抗剂RC-3095 [D-Tpi(6)，Leu(13)ψ(CH2NH)Leu(14)-蛙皮素(6-14)]、RC-3910-II [D-Tpi(6)，Leu(13)ψ(CH2N)Tac(14)-蛙皮素(6-14)]、RC-3940-II [Hca(6)，Leu(13)ψ(CH2N)Tac(14)-蛙皮素(6-14)]、RC-3950-II [D-Phe(6)，Leu(13)ψ(CH2N)Tac(14)-蛙皮素(6-14)]、生长抑素类似物RC-160（D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2）或RC-3095与RC160的组合进行为期两个月的治疗。所有肽均不同程度地抑制胰腺癌，减少患肿瘤动物的数量，使肿瘤胰腺的重量降低40 - 55%，并减少作为细胞增殖率指标的嗜银核仁组织区（AgNOR）数量。RC-3095与RC-160联合治疗对肿瘤的抑制效果并不优于单一肽。在新型蛙皮素/胃泌素释放肽拮抗剂中，RC-3940-II具有最强的抑制作用。RC-3950-II和RC-3095引起的抑制作用相似，但RC-3910-II效果较差。蛙皮素/胃泌素释放肽拮抗剂的肿瘤抑制活性与其对肿瘤细胞上蛙皮素受体的结合亲和力相关。RC-3940-II在浓度为0.96 nM时可使[I-125-Tyr(4)]蛙皮素与肿瘤细胞膜的特异性结合受到50%的抑制，而RC-3950-II的半数抑制浓度（IC50）为5.27 nM，RC-3095为12.94 nM。我们的研究结果表明，除RC-3095外，其他蛙皮素/胃泌素释放肽拮抗剂，如RC-3950-II，尤其是RC-3940-II，可进一步开发用于治疗人类胰腺癌。
