Effects of new bombesin antagonists given singly or in combination with a somatostatin analog on nitrosamine-induced pancreatic cancers in hamsters

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-Tpi⁶,Leu¹³'Ψ(CH₂NH)Leu¹⁴-bombesin(6-14)], RC- 3910-II [D-Tpi⁶,Leu¹³'Ψ(CH₂N)Tac¹⁴-bombesin(6-14)], RC-3940-II [Hca⁶,Leu¹³'Ψ(CH₂N)Tac¹⁴-bombesin(6-14)], RC-3950-II [D- Phe⁶,Leu¹³'Ψ(CH₂N)Tac¹⁴-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 RC-160. 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 [¹²⁵I-Tyr⁴]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.