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Metabolic stability and tumor inhibition of bombesin/GRP receptor antagonists
T P Davis1, S Crowell, J Taylor
1Department of Pharmacology, University of Arizona, College of Medicine, Tucson 85724.
Abstract:
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 [Psi13,14]BN. Here several BN analogues were solid-phase synthesized and incubated with intact SCLC cells at 37 degrees 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. [Psi13,14]BN was found to be very stable to metabolic enzymes (T1/2 = 646 mm) and also inhibited SCLC xenograft formation in vivo in a dose-dependent manner. When [Psi13,14]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 [Psi13,14]BN may be useful for the treatment of SCLC.
Insights
Bombesin/gastrin-releasing peptide (BN/GRP) receptor antagonists, like [Psi13,14]BN, show promise for treating small cell lung cancer (SCLC). This study found [Psi13,14]BN to be metabolically stable and effective in inhibiting SCLC growth.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Small cell lung cancer (SCLC) relies on an autocrine growth loop involving bombesin/gastrin-releasing peptide (BN/GRP).
- BN/GRP receptor antagonists offer a potential therapeutic strategy to disrupt this SCLC growth cycle.
Purpose of the Study:
- To synthesize and evaluate the enzymatic stability of novel BN analogues.
- To assess the efficacy of [Psi13,14]BN as a BN/GRP receptor antagonist in SCLC models.
Main Methods:
- Solid-phase synthesis of BN analogues.
- Incubation of analogues with SCLC cells to determine metabolic stability via HPLC analysis.
- Inhibition of 125I-GRP binding and SCLC xenograft formation assays.
Main Results:
- Metabolic half-lives for six analogues ranged from 154 to 1388 minutes.
- [Psi13,14]BN demonstrated significant metabolic stability (T1/2 = 646 min).
- [Psi13,14]BN inhibited SCLC xenograft formation dose-dependently and 125I-GRP binding (IC50 = 30 nM).
Conclusions:
- BN/GRP receptor antagonists, exemplified by the stable analogue [Psi13,14]BN, hold potential for SCLC treatment.
- The metabolic stability and in vivo efficacy suggest [Psi13,14]BN is a promising candidate for further SCLC therapeutic development.