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.

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