It has been demonstrated that bombesin/GRP antagonist D-Tpi(6),Leu(13)psi(CH2NH) Leu(14)-BN(6-14) (RC-3095) inhibits effectively the growth of pancreatic cancer and other tumors in experimental animals and in cell cultures. In an attempt to develop antagonists with still greater antitumor activity, several new pseudononapeptide bombesin/GRP antagonists containing C-terminal Leu psi(CH2N)Tac-NH2 have been synthesized in our laboratory. In this study, we investigated the ability of four Leu(13)psi(CH2N)Tac(14)-BN(6-14) antagonists to inhibit the binding of bombesin to specific receptors for bombesin/GRP on CFPAC-1 human pancreatic cancer cells. Receptor binding assays were performed by incubating CFPAC-1 cells (5x10(4) cells/well) with 0.5 nM [I-125]-Tyr(4)-bombesin in the absence or presence of (1 pM to 10 mu M) unlabeled bombesin, GRP(14-27) and various antagonists for 2 h at 22 degrees C. Displacement assays showed that antagonist D-Tpi(6),Leu(13)psi(CH2N)Tac(14)-BN(6-14) (RC-3910-II) with a similar structure to RC-3095, but a different C-terminal, had a binding affinity to CFPAC-1 cells 15 times higher than RC-3095. Three other antagonists, RC-3925-II, RC-3940-II and RC-3950-II contained the same C-terminal Leu psi(CH2N)Tac-NH2 as RC-3910-II, but had different N-terminal residues: D-Cpa, Hca and D-Phe, respectively. Among them, Hca(6),Leu(13)psi(CH2N)Tac(14)-BN(6-14) (RC-3940-II) showed the highest binding affinity to the receptors on CFPAC-1 cells, which was 50 times higher than that of RC-3095 or 3 times greater than RC-3910-II. Our findings suggest the merit of further investigation of pseudononapeptide bombesin/GRP antagonist RC-3940-II ind related analogs for a possible development of a new hormonal therapy for pancreatic cancer.

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