TARGETED ANTITUMOR THERAPY WITH THE SCORPION VENOM CHLOROTOXIN

Chlorotoxin (CTX) is a 36-amino-acid neurotoxin isolated from the venom of the giant yellow Israeli scorpion Leiurus quinquestriatus. The peptide preferentially binds to human malignancies, but not to normal human tissues. Annexin A2 is a receptor for CTX. CTX binding results in internalization and subsequent downregulation of matrix metalloproteinase-2 (MMP-2) and chloride channel protein 3 (CIC-3) on malignant cells. In turn, this inhibits migration of glioma cells, induces antiangiogenic effects and potentially increases the efficacy of other therapies. A synthetic version of this peptide, TM-607 (Morphotek, Inc.), has been covalently linked to iodine 131 ([I-131]-TM-601) as a means of targeting radiation to tumor cells. Phase clinical trials in patients with recurrent glioma indicate that [I-131]-TM-601 binds malignant glioma with high affinity and a long duration. The therapy appears safe, minimally toxic and may improve survival. The fluorescent bioconjugate CTX:Cy5.5 has been developed as a "tumor paint" to detect tumors and maximize the extent of removal during surgery. CTX has also been conjugated to magnetic nano particles for MRI detection and intracellular delivery of DNA for gene therapy. Due to its small size, selective tumor binding properties, minimal toxicity and relative ease of manipulation, CTX represents a potentially important targeting agent for many cancers.