David Grdina, Ph.D.

Tumor Heterogeneity and its Role in Tumor Resistance to Radiation and Chemotherapy

Research Summary

Dr David Grdina has investigated the antimutagenic and anticarcinogenic properties of a class of agents known as phosphorothioates. Investigations are focused at identifying the underlying mechanism of action of these drugs in an attempt to identify and characterize novel markers of chemopreventive effectiveness. Even at concentrations as low as 40 micro-molar, WR-1065, the thiol form of amifostine, can inhibit cellular proliferation. This is due in part to its ability to inhibit topoisomerase II activity indirectly via a phosphorylation-mediated process. The polyamine spermine has also been found to be effective, at similar intracellular concentrations, in inhibiting topoisomerase II activity. In addition, Dr Grdina's laboratory has determined that these compounds can affect chromatin stabilization, enhance the fidelity of inducible DNA repair systems, and modulate gene expression. Specifically, using the methods of differential display, DNA sequencing, and Northern analysis, WR-1065, at concentrations as low as 40 M, can enhance gene expression of Mn superoxide dismutase (SOD), thymidine kinase, Pctaire kinase, and nuclear lamin A and can reduce gene expression of c-myc. This thiol also affects the activation of the redox-controlled transcription factor NFkB. The working hypothesis put forth by this laboratory is that aminothiol drugs, and in particular their disulfide metabolites, are acting in the same manner as polyamines to affect intracellular processes related to DNA synthesis and repair.

Selected Papers

Grdina DJ, Kataoka Y, Murley JS, Hunter N, Weichselbaum RR and Milas L. (2002). Inhibition of Spontaneous Metastases Formation by Amifostine. International Journal of Cancer, 97:135-141.

Grdina DJ, Murley JS, Katoaka Y and Calvin DP. (2002). Differential Activation of Nuclear Transcription Factor kB, Gene Expression, and Proteins by Amifostine's Free Thiol in Human Microvascular Endothelial and Glioma Cells. Seminars in Radiation Oncology, 12 (No 1, Suppl. 1): 103-111.

Khodarev NN, Yu J, Nodzenski E, Murley JS, Kataoka Y, Brown CK, Grdina DJ and Weichselbaum RR. (2002). Method of RNA purification from endothelial cells for DNA array experiments. BioTechniques, 32:316-320.

Kataoka Y, Murley JS, Khodarev NN, Weichselbaum RR and Grdina DJ. (2002). Activation of the Nuclear Transcription Factor kB (NFkB) and Differential Gene Expression in U87 Glioma Cells Following Exposure to the Cytoprotector Amifostine. International Journal of Radiation Oncology, Biology, and Physics, 53:180-189.

Murley JS, Kataoka Y, Weydert CJ, Oberley LW and Grdina DJ. (2002). Delayed Cytoprotection Following Enhancement of MnSOD Gene Expression in SA-NH Mouse Sarcoma Cells Exposed to Amifostine's Active Metabolite WR1065. Radiation Research,158:101-109.

Grdina DJ, Kataoka Y, Murley JS, Swedberg K, Lee JY, Hunter N, Weichselbaum RR and Milas L. (2002). Anti-Metastatic Effectiveness of Amifostine Therapy Following Surgical Removal of SA-NH Tumors in Mice. Seminars in Oncology, 29#6 (Suppl. 18).

Grdina DJ, Murley JS and Kataoka Y. (2002). Radioprotectants: Current Status and New Directions.Oncology, 63(suppl 2):2-10.

Grdina DJ, Murley JS, Kataoka Y and Epperly W. (2002). Relationships Between Cytoprotection and Mutation Prevention by WR-1065, Military Medicine, 167(suppl 1):51-53.

Elas M, Parasca A, Grdina DJ, Halpern HJ. (2003). Oral Administration Is As Effective As Intraperitoneal Administration of Amifostine in Decreasing Nitroxide EPR Signal Decay In Vivo, Biochemica et Biophysica Acta, 1637:151-155.