Targeting human colorectal cancer cells using radiolabeled E. coli heat-stable enterotoxin analogs [abstract]
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The guanylate cyclase C (GC-C) receptor protein is normally expressed at high levels on the luminal surface of the gastrointestinal epithelium. Binding of the endogenous peptides guanylin and uroguanylin to GC-C initiates a signaling cascade, leading to phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR). Phosphorylation of CFTR opens the channel, resulting in net flow of water and Cl- ions into the intestinal lumen. Perhaps via gene transfer from vertebrate hosts, enteropathogenic strains of E. coli have evolved a homologous peptide, the E. coli heat-stable enterotoxin (STh), which has the highest affinity for the GC-C receptor of any known ligand. Expression of GC-C persists in mucosal cells that have undergone malignant transformation, providing a specific marker for human colorectal cancer. Presentation of the GC-C receptor on the surface of colorectal cancer cells therefore provides a specific target for binding of radiolabeled heat-stable enterotoxin analogs. The goal of the work presented here is to develop analogs of the STh with N-terminal pendant chelating moieties that can deliver imaging and therapeutic radionuclides to primary and metastatic colon cancer tissues. Data will be presented relating to a modified STh analog. This analog has been synthesized and labeled with nonradioactive indium and the radioisotope 111In. The analog was evaluated for receptor binding affinity in vitro, as well as for in vivo pharmacokinetic characteristics in SCID mice with human colon cancer xenografts. Receptor binding affinity was in the nanomolar range for both labeled and unlabeled peptides, and in vivo results demonstrated localization of radiolabel within the tumor mass.