Cell & Stem Cell Research

Biography

Biography: Paul J Davis

Abstract

Integrin αvβ3 is concentrated and activated on the surface of tumor cells and dividing endothelial cells where it is critical to cell-cell and cell-extracellular matrix protein interactions and to function of cell surface vascular growth factor receptors. Exploration of the functions of a receptor for thyroid hormone and hormone analogues on the integrin has linked hormone analogues to regulation of expression of genes relevant to angiogenesis to differential regulation of apoptosis (pro- and anti-apoptosis) and to repair of double-strand DNA breaks. Tetraiodothyro-acetic acid (tetrac) is a naturally-occurring deaminated analogue of L-thyroxine (T4) that, when covalently bound to a nanoparticle that precludes its cellular uptake acts exclusively at αvβ3 via a variety of signal transducing kinases and other mechanisms as an anti-cancer/anti-angiogenesis agent. We report here the action of systemic nanoparticulate tetrac (Nano-diamino-tetrac, NDAT or Nanotetrac) on human glioblastoma (U87MG) xenograft size and histology. Ten days’ daily subcutaneous treatment of tumor-bearing nude mice with NDAT (1 mg tetrac-equivalent/kg/day) resulted in a 38% decrease in tumor volume in situ and 47% decrease in tumor weight at sacrifice (p<0.01 vs. control). Blinded histopathologic review of tumors from control and treated animals has revealed essentially complete loss of vascularity without hemorrhage and consequent 5-fold increase in necrotic cells in drug-exposed tumors. There was 4.5-fold increase in apoptotic cells in treated tumors. Changes were significant at p<0.01. NDAT is a novel nanopharmaceutical that acts exclusively on cancer and endothelial cell surfaces to induce apoptosis and systematic devascularization with necrosis.