131I-Chlorotoxin

Excerpt

Chlorotoxin (CTX) is a neurotoxin comprising 36 amino acids and is isolated from the venom of Leiurus quinquestriatus, a scorpion of the Buthidae family. A characteristic feature of the peptide is the four disulfide bonds that give it a tight tertiary structure and a single tyrosine residue that can be iodinated. Originally, CTX was described as a calcium channel blocker (1). Later, selective and specific binding of CTX to glioma cells was demonstrated by immunochemical techniques, and radiolabeled CTX was shown to bind only to tumor cells in a mouse xenograft glioma tumor model (1). On the basis of in vitro studies, CTX was discovered to bind only to malignant (glioma) and not normal (glial) cells, indicating that the toxin had a binding specificity for embryologically related tumors, particularly those of neuroectodermal origin (2). Using a recombinant form of the toxin, it was shown that CTX binds to and reduces the activity of a matrix metalloproteinase (MMP) that is associated with and indirectly regulates functioning of the chloride channels on cell membranes (3, 4). Deshane et al. showed that isoform 2 of the MMP (MMP2) was the specific cellular receptor for CTX and that the ligand did not bind to the other MMPs also expressed on the glioma cells (4). In other in vitro studies it was shown that CTX reduced the migration ability of glioma cells through tight extracellular spaces in the brain tissue by inhibition of the MMP2, because this prevented the cells from shrinking and releasing from the extracellular matrix (5).

The MMP2 enzyme activity was observed to be significantly elevated in malignant glioma cells compared to low-grade glioma and normal brain tissues, and the upregulation correlated with the malignant progression of human gliomas in vivo (6). In the same study, which used immunohistochemical techniques, MMP2 was shown to be localized only in the cells and vasculature of malignant glioma tumors. These observations explained the specificity and selectivity of CTX binding to the malignant glioma tumors observed by the various investigators. Currently, resection of the tumor is the only effective treatment for glioma, but the tumor often reappears at the same spot or close to it because not all neoplastic cells can be completely removed during surgery.

Because of its specificity and selectivity for glioma cells, a synthetic version of CTX, TM-601, was generated either by production in Escherchia coli or by chemical synthesis (2, 4, 7). The peptide has been radiolabeled with radioactive iodine (¹³¹I) to obtain ¹³¹I-TM601 and used for preclinical and clinical imaging and radiotherapy of malignant glioma (8, 9). The iodinated peptide is currently being evaluated in clinical trials in the United States for the treatment of solid tumors or recurrent high-grade gliomas in humans (10).