pg-97-269 and Lung-Neoplasms

Vasoactive intestinal peptide (VIP) binds to two receptors, VPAC1 and VPAC2. Non-selective VIP antagonists have been shown to inhibit human cancer cell proliferation and reduce tumor growth in mice. Many human cancers over-express VPAC1 but not VPAC2. We show that VPAC1-selective antagonists can inhibit human cancer cell proliferation and identify five positions in the VPAC1-selective antagonist PG 97-269 that may be responsible for VPAC1 selectivity. Position 16 appears to be particularly critical for selectivity, as demonstrated in the replacement of Arg16 of PG 97-269 with the native VIP amino acid; this single change results in greatly reduced VPAC1 binding and selectivity. Finally, we show that site-specific conjugation with a 22kDa polyethylene glycol (PEG) at the C-terminus of VPAC1-selective antagonists further improves VPAC1-selective binding and has minimal effect on antagonistic activity. Our studies have further solidified VPAC1 as a cancer target and offer the possibility of generating highly potent VPAC1-selective antagonists with minimal number of mutations to reduce the risk of immunogenicity and potentially prolonged duration of action to allow more efficient treatment regimen.

Topics: Amino Acid Sequence; Animals; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Electrophoresis, Polyacrylamide Gel; Humans; Lung Neoplasms; Molecular Sequence Data; Peptide Fragments; Polyethylene Glycols; Protein Binding; Radioimmunoassay; Receptors, Vasoactive Intestinal Polypeptide, Type I; Sequence Homology, Amino Acid; Structure-Activity Relationship; Vasoactive Intestinal Peptide