David Grdina, Ph.D.

Professor of Radiation and Cellular Oncology

Research Summary

Dr. Grdina’s research program is focused on developing new effective strategies to prevent therapy induced secondary cancers in patients having a good prognosis and a relatively long life expectancy. Research activities currently being pursued in this program include: 1) development and characterization of novel phosphorothioate radioprotective drugs such as phosphonol for use in the prevention of radiation- and chemotherapy induced secondary malignancies; 2) prevention and treatment of metastatic disease utilizing thiol containing cytoprotective drugs; 3) protection against radiation induced genomic instability in non-tumor cells through the exploitation of a novel paradigm identified as “the delayed radioprotective effect.” This effect is mediated by the activation of NFκB through the oxidation of cysteine residues on its p50 and p65 subunits that leads subsequently to the elevated transcription of MnSOD that result in a 15 to 20 fold elevation in intracellular levels of active MnSOD protein 24 hr. later. Elevation of MnSOD levels localized within mitochondria appears to affect signaling pathways involved in homologous recombination processes within nuclear DNA that can lead to genomic instability. Understanding this process is a major goal of this program. Thiols demonstrated to be effective in inducing this effect are N-acetyl-L-cysteine, captopril, mesna, and amifostine. Since each of these is used clinically, the possibility exists that patients exposed to any of these agents during radiation therapy may exhibit an altered radiation resistant phenotype. If this effect is limited to normal tissues, it may lead to a reduction in normal tissue complications. However, if the protective effect extends to tumors, the possibility exists that tumor response to therapy will be reduced. Under in vitro conditions, each of these agents enhanced tumor cell survival at a 2 Gy dose by 20 to 40%. Such an effect in vivo during a course of radiation therapy would be disastrous. Experiments are being performed to extend these studies to well characterized animal model systems. The effects of phosphorothioate drugs on gene expression are also being carried out with special emphasis on effects related to genes under the control of the NFκB transcription factor. This is important because all thiol containing drugs evaluated thus far are effective activators of NFκB, a transcription factor known to be involved in not only survival pathways but also inflammatory responses. 

Publications

  • Murley, J.S., K.L. Baker, R.C. Miller, T.E. Darga, R.R. Weichselbaum, D.J. Grdina. SOD2-mediated adaptive responses induced by low-dose ionizing radiation via TNF signaling and amifostine. Free Radical Biol. Med. 51: 1918-1925, 2011.
  • Fu, P., J.S. Murley, D.J. Grdina, A.A. Birukova, K.G. Birukov. Induction of cellular antioxidant defense by amifostine improves ventilator-induced lung injury. Crit. Care Med. 39(12):2711-2721, 2011.
  • Murley, J.S., Y. Kataoka, R.C. Miller, J.J. Li, G. Woloschak, D.J. Grdina. SOD2-mediated effects induced by WR1065 and low-dose ionizing radiation on micronucleus formation in RKO human colon carcinoma cells. Radiat. Res. 175: 57-65, 2011.
  • Dziegielewski, J., W. Goetz, J.S. Murley, D.J. Grdina, W.F. Morgan, and J.E. Baulch. Amifostine metabolite WR-1065 disrupts homologous recombination in mammalian cells. Radiat. Res.,173:175-183, 2010.
  • Hooker, A.M., D.J. Grdina, J.S. Murley, B.J. Blyth, R.J. Ormsby, E. Bezak, K.A. Giam, P.M. Sykes. Low doses of amifostine protect from chromosomal inversions in spleen in vivo when administered after an occupationally relevant X-radiation dose. Int. J. Low Radiat., 6(1):43-56, 2009.