Howard Halpern, M.D., Ph.D.

Oxygen-Centered Radicals in Signal Pathways and Toxicity.

Research Summary

Our laboratory is using in vivo electron paramagnetic resonance (EPR) spectrosocopy to measure and image oxygen concentrations in tumors of living animals and to measure the evolution of radicals in tissues in response to radiation and possible ischemia. Because EPR is a magnetic resonance technique, we can use it to image as well as measure oxygen concentrations. Though spectroscopy is relatively well developed, imaging is an emerging technology capable of showing evidence of tumor oxygenation heterogeneity. We hope to be able to see heterogeneity of hydroxyl free radical evolution in response to radiation. We have actually generated a one-dimensional image of oxygen concentrations in an FSa fibrosarcoma in the leg of a C3H mouse. Oxidative signaling pathways underlie the oxidative stress response. For a wide variety of systems, the proximate signal in the oxidative response is believed to be an oxygen-centered free radical, which may, in the case of superoxide or hydroxyl, be evanescent or, in the case of a lipid peroxide, be more stable. But the role of free radicals in biologic signaling remains a belief or hypothesis until such free radicals are measured and the systematics of their evolution are connected sensibly to the biologic processes with which they are believed to be involved. Using EPR in combination with spin trapping, we were recently able to detect the evolution of hydroxyl radicals in the leg tumor of a living mouse.

Selected Papers

Halpern HJ, Peric M, Yu C, Bales BL. (1993). Rapid evaluation of parameters from inhomogeneously broadened EPR spectra. J Magn Reson, 103:13-22.

Halpern HJ, Yu C, Peric M, Barth E. (1994). Oxymetry deep in tissues with low frequency electron paramagnetic resonance. Proc Natl Acad Sci USA, in press.

Halpern H.J. Peric M. Yu C. Barth E.D. Boisvert W. Makinen M.W. Pou S. Rosen G.M. (1996). In-Vivo Murine pharmacodynamics using very low frequency electron paramagnetic resonance imaging. Biophys J. 71:403-409.

Roeske JC, Mundt AJ, Halpern HJ, Sweeney P, Sutton H, Powers C, Rotmensch J, Waggoner S, Weichselbaum RR. (1997). Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: a dosimetric analysis. Int. J. Radiat. Oncol. Biol. Phys.37:351-358.

Pou S, Halpern HJ, Tsai P, Rosen GM. (1999). Issues pertinent to the in vivo in situ trapping of free radicals.  Accounts Chem. Res. 32:155-161.

Halpern HJ, Chandramouli GVR, Barth ED, Yu C, Peric M, Grdina DJ, Teicher BA. (1999). Diminished aqueous microvisosity of tumors in murine models measured with in vivo radiofrequency EPR. Cancer Research, 59:5836-41.

Yong L, Harbridge J, Quine RW, Rinard GA, Eaton SS, Eaton GR, Mailer C, Barth E, Halpern HJ. (2001). Electron Spin Relaxation of Triarylethyl Radicals in Fluid Solution. J. Magn. Reson. 152:156-161.

Williams BB, al Hallaq H, Chandramouli GVR, Barth ED, Rivers JN, Lewis M, Galtsev VE, Karczmar GS and Halpern HJ. (2002). Imaging Spin Probe Distribution in the Tumor of a Living Mouse with 250 MHz EPR:  Correlation with BOLD MRI. Magn. Reson. Med. 47:634-638.

Rinard GA, Quine RW, Eaton SS, Eaton GR, Barth ED, Pelizzari CP, Halpern HJ. (2002). Magnet and gradient coil system for low-field EPR imaging.  Concepts in Magnetic Resonance 15:51-58.

Iwama T, Reddy TJ, Halpern HJ, Rawal VH. (2002). General synthesis of persistent trityl radicals for EPR imaging of biological systems.   J. Org. Chem.:67:4635-4639.

Elas M,  Williams BB,  Parasca A, Mailer C,  Pelizzari CA, Lewis MA, River JA,  Karczmar GS,  Eugene D. Barth,  Halpern HJ. (2002). Quantitative Tumor Oxymetric Images from 4-Dimensional  Electron Paramagnetic Resonance Imaging (EPRI): Methodology and Comparison with Blood Oxygen Level Dependent (BOLD) MRI.  Magn. Reson. Med. :49:582-591.

Rosen GM, Porasuphatana S, Tsai P, Ambulos, Galtsev VE, and Halpern HJ. (2003). Dendrimeric-containing nitronyl nitroxides as spin traps for nitric oxide: Synthesis, kinetic and stability studies.   Macromolecules: 36:1021-1027.

Elas M, Parasca A, Grdina DJ, and Halpern HJ. (2003). Oral administration is as effective as intraperitoneal administration of amifostine in decreasing nitroxide EPR signal decay in vivo. Biochem. Biophys. Act:1637(2):151-155.

Mailer C, Robinson BH, Halpern, HJ. (2003). Spectral Fitting: The extraction of crucial information from a spectrum and a spectral image.   Magn. Reson. Med. 49:1175-1180.

Tsai P, Ichikawa K, Mailer C, Pou S, Halpern HJ, Robinson BH,  Nielsen R, Rosen GM. (2003). Esters of 5-Carboxyl-5--Methyl-1-Pyrroline N-Oxide: A Family of Spin Traps for Superoxide.  J. Org. Chem. 68:7811-7818.

Carson PL, Giger M, Welch MJ, Halpern H, Kurdziel K, Vannier M, Evelhoch JL, Gazelle GS, Seltzer SE, Judy P, Hendee WR, Bourland JD. (2003). Biomedical imaging research opportunities workshop: report and recommendations.  Radiology: 229:328-339.

Al-Hallaq HA, Zamora MA, Fish BL, Halpern HJ, Moulder JE, Karczmar GS. (2003). Using high spectral and spatial resolution bold MRI to choose the optimal oxygenating treatment for individual cancer patients. Adv Exp Med Biol. 530:433-40.

Dreher MR, Elas M, Ichikawa K, Barth ED, Chilkoti A, Rosen GM, Halpern HJ, Dewhirst M. (2004). Nitroxide conjugate of a thermally responsive elastin-like polypeptide for non-invasive thermometry. Med. Phys. 31:2755-62.

Bowman MK, Mailer C, Halpern HJ. (2005). The solution conformation of triarylmethyl radicals. J. Magn. Reson. 172:254-6.

Williams BB, Pan X, Halpern HJ. (2005). EPR Imaging: The relationship between CW spectra acquired from an extended sample subjected to fixed stepped gradients and the Radon transform of the resonance density.  J. Magn. Reson. 174:88-96.

Mailer C, Subramanian VS, Pelizzari CA and Halpern HJ. (2006). Spin echo spectroscopic EPR imaging.  Magn. Reson. Med. 55,  904-12.

Elas M, Ahn K-H,Parasca A, Barth ED, Lee D, Haney C, Halpern HJ. (2006).Electron paramagnetic resonance oxygen images correlate spatially and quantitatively with Oxylite^TM oxygen measurements.  Clin. Ca. Res.12: 4209-4217.