Gastrin releasing polypeptide (GRP) has been shown to be an autocrine facto for small cell lung carcinoma (SCLC) cells both in vivo and in vitro. This polypeptide has a high degree of sequence homology with the carboxy termina domain of bombesin (BN). Both GRP and BN are synthesized as larger precurso molecules. In order for the pro-molecule to become bioactive, further enzymatic processing is required, i.e. , truncation as well as the formatio of a C-terminal amide. The latter requires the presence of an amidating enzyme. As a first step toward designing a potential antagonist for the growth of SCLC cells, we examined the requirements for the ligand binding to the BN receptor by synthesizing a series of C-terminal domain analogues of BN. Contrary to previous reports, we found that the precursor itself is a very weak agonist. Furthermore, based on our BN receptor binding data, th mode of BN receptor binding does not occur by an end-on approach but rather side-on. Further work on the isolation and characterization of GRP amidatin enzyme from several established SCLC lines is ongoing.
