Abstract
We developed a bacterial expression system to produce a recombinant disintegrin, vicrostatin (VCN), whose structure is based on a natural disintegrin isolated from southern copperhead snake venom. Our goal is to develop VCN for potential clinical translation as an anti-cancer agent. VCN is a peptide of 69 amino acids with a single tyrosine residue. We have employed VCN as integrin-targeted radionuclide therapy (brachytherapy) for treatment of glioblastoma (GBM, glioma). GBM is a deadly brain cancer that doesn’t discriminate between sexes and knows no age limit. We established that the tyrosine residue in VCN can be radioiodinated with full retention of bioactivity. 131I-VCN was utilized for integrin-targeted radionuclide therapy using mouse models of glioma. The combination of radioiodinated VCN plus temozolomide (a DNA alkylating agent) significantly prolonged survival of glioma-bearing mice. We also obtained similar results using an immunocompetent mouse model and a murine glioma cell line. In summary, as demonstrated in studies reported here we have shown that VCN as targeted radionuclide therapy for GBM has significant translational potential for therapy of this deadly disease.
Highlights
Glioblastoma multiforme (GBM) affects males and females and knows no age barrier; it accounts for more than 50% of all human primary brain tumors
In the present report we describe our findings with the use of radioiodinated-VCN as a form of integrin-targeted radionuclide therapy in combination with temozolomide in murine models of human GBM
The tyrosine is shown at residue 51 in VCN, which is the site of radioiodination of the peptide
Summary
Glioblastoma multiforme (GBM) affects males and females and knows no age barrier; it accounts for more than 50% of all human primary brain tumors. Chemotherapy, and radiation therapy GBM remains a highly invasive cancer, and the average life span is only 12 to 15 months from time of diagnosis. Increasing incidence of GBM is one of the prime factors driving the development of new therapeutic strategies. GBM is considered the most aggressive form of brain cancer; it grows rapidly and spreads into the normal brain. The National Cancer Institute (NCI) estimates that 23,880 adults will be diagnosed with brain and other nervous system forms of cancer in 2018. The NCI estimates that in 2018, 16,830 of these diagnoses will result in death [1]
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