Metabolic stability and tumor inhibition of bombesin/GRP receptor antagonists

Small cell lung cancers (SCLC) synthesize and secrete bombesin/gastrin releasing peptide (BN/GRP). The autocrine growth cycle of BN/GRP in SCLC can be disrupted by BN/GRP receptor antagonists such as [Psi^13,14]BN. Here several BN analogues were solid-phase synthesized and incubated with intact SCLC cells at 37°C in RPMI medium in a time-course fashion (0-1080 minutes) to determine enzymatic stability. The proteolytic stability of the compounds was determined by subsequent HPLC analysis. The metabolic half-life ranged from 154 minutes to 1388 minutes for the six analogues studied. [Psi^13,14]BN was found to be very stable to metabolic enzymes (T 1 2 = 646 mm) and also inhibited SCLC xenograft formation in vivo in a dose-dependent manner. When [Psi^13,14]BN was incubated with NCI-H345 cells, it inhibited ¹²⁵I-GRP binding with an IC₅₀ value of 30 nM. These data suggest that BN/GRP receptor antagonists such as [Psi^13,14]BN may be useful for the treatment of SCLC.