Abstract 3447: Tetrac (tetraiidothyroacetic acid) decreases in vitro x-ray survival of a human medullary thyroid cancer cell line under oxic and hypoxic conditions

Abstract

Abstract In 2009 we showed that 2 µM tetrac given for 1 hour at 37oC prior to 250 kVP x-irradiation sensitized GL261 murine brain tumor cells. Radiosensitization was accomplished by increasing the alpha component in the linear-quadratic equation of cell survival (Cell Cycle, 8:2586-91). In 2011, we showed that tetrac also sensitized U87MG human brain tumor cells to 250 kVp x-rays (Cell Cycle, 10: 352-57). Again radiosensitization was accomplished by an increase in the αx-ray component. Tetrac also inhibited the repair of DNA double strand breaks in U87MG cells. However, tetrac which binds to the αvβ3 integrin receptor and inhibitssignaling from the αvβ3 receptor, penetrates the cell and has a thyromimetic effect which offsets radiosensitization. In this regard, we synthesized a nanoparticle tetrac formulation termed Nano-T. Nano-T also binds to the αvβ3 receptor but does notpenetrate the cell. Nano-T causes radiosensitization in vitro in H522 lung cancer cells, producing an added benefit compared to tetrac. We have also shown that daily treatment of in vivo human-MTC (h-MTC) solid tumors in mice with Nano-T for 20 days produced significant growth inhibition. It is our intent to combine Nano-T with ionizing radiation in vivo, and we have begun by studying the effects of tetrac on h-MTC cells in vitro. These h-MTC cells are show an in vitro cell culture doubling time of 96.2 hours and a clonogenicity of 3.16%. We irradiated cells in exponential growth with 250 kVp X-rays. Below we give the LQ survival parameters, and the surviving fraction at 2 Gy (SF2). Table 1. Initial Results of 250 kVp Single Dose X-irradiation on h-MTC CellsIn Vitro without and with Tetrac ≤ α SF2 Tetrac Oxygen (Gy-1 x 10-1) (Gy-2 x 10-2) Enhancment Enhancement Factor Factor Without Tetrac Oxic Cells - 0.033 0.0256 0.901 2.55 Hypoxic Cells 0.030 0.0023 0.922 With Tetrac Oxic Cells 0.472 0.0495 0.330 2.84 2.60 Hypoxic Cells 0.013 0.0256 0.803 2.84 First, h-MTC cells irradiated as oxic or hypoxic, exponentially growing cells are very radioresistant suggesting a large capacity to repair radiation damage. Second, tetrac sensitized both oxic and hypoxic h-MTC cells. These characteristics speak to our proposed Nano-T in treatment of h-MTC tumors in vivo. Nano-T should increase the radiosensitivity of both oxic and hypoxic cells and should also decrease the repair of radiation damage in conventional fractionated radiation therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3447. doi:1538-7445.AM2012-3447