New pseudononapeptide bombesin antagonists with C-terminal LeuΨ(CH2N)Tac-NH2 show high binding affinity to bombesin/GRP receptors on CFPAC-1 human pancreatic cancer cells

Renzhi Cai, Y. Qin, T. Ertl, A. V. Schally

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

It has been demonstrated that bombesin/GRP antagonist D-Tpi6,Leu13Ψ(CH2NH) Leu14-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 LeuΨ(CH2N)Tac-NH2 have been synthesized in our laboratory. In this study, we investigated the ability of four Leu13Ψ(CH2N)Tac14-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 (5 x 104 cells/well) with 0.5 nM [125I]-Tyr4-bombesin in the absence or presence of (1 pM to 10 μM) unlabeled bombesin, GRP(14-27) and various antagonists for 2 h at 22°C. Displacement assays showed that antagonist D-Tpi6,Leu13Ψ(CH2N)Tac14-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 LeuΨ(CH2N)Tac-NH2 as RC-3910-II, but had different N-terminal residues: D-Cpa, Hca and D-Phe, respectively. Among them, Hca6,Leu13Ψ(CH2N)Tac14-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 and related analogs for a possible development of a new hormonal therapy for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1165-1172
Number of pages8
JournalInternational journal of oncology
Volume6
Issue number6
StatePublished - Jan 1 1995
Externally publishedYes

Keywords

  • Bombesin
  • Bombesin antagonist
  • Gastrin-releasing peptide
  • Pancreatic cancer
  • Receptors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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