Conventional cancer therapeutic regimens such as radiation or chemotherapy attempt to exploit physiological differences in oxygenation, redox status, and vasculature between normal and malignant tissues to provide selective killing of the tumor. Thus, methods that detect and quantify these metabolic differences should enable the development of more efficacious treatment strategies. Since localized tumor hypoxia is associated with cancer treatment failure, obtaining spatial information on such tumor volumes should also be valuable. The applicant has recently developed electron paramagnetic resonance imaging (EPRI) instrumentation capable of performing non-invasive physiological measurements in living objects. This technique can be adapted to measure in vivo tissue oxygenation and redox status using appropriate spin probes. Nitroxides, a class of stable free radical compounds, have been extensively used as probes for EPRI. Recently nitroxides have also been shown to provide selective radio protection of normal tissues, presumable due to their differential bioreduction rates of tumor versus normal tissue. Preliminary experiments have shown the feasibility of obtaining three-dimensional (3D) images of the pharmacokinetics of nitroxide distribution and oxygenation in murine tumor models. The goal of the present proposal is to utilize these new EPRI techniques as a noninvasive tool to evaluate tumor pathophysiology.
The Specific Aims are to: (i) Measure pharmacokinetics of redox sensitive nitroxides in normal and tumor tissues in vivo to evaluate heterogeneity in redox status. (ii) Perform in vivo 3D spatial EPRI of tumors with appropriate spin probes to obtain morphological (tissue heterogeneity) and mapping of physiological information as redox status and tissue perfusion. (iii) Perform spectral-spatial EPRI to obtain spatial mapping of oxygenation of malignant tissue and compare with normal tissue. (iv) Measure tumor hypoxic fractions for different tumor types using EPRI and compare with those obtained from other techniques such as microelectrode, in vitro radiobiology and nitromidazole binding. (v) Examine in vivo tumor vasculature using vasculature-specific spin labels and manipulations using vasoconstrictor and vasodilators on tissue perfusion and oxygenation. (vi) Obtain tissue reoxygenation profiles in tumors after therapeutic regimens such as radiation treatment or chemotherapeutic agents.
| Vikram, Deepti S; Bratasz, Anna; Ahmad, Rizwan et al. (2007) A comparative evaluation of EPR and OxyLite oximetry using a random sampling of pO(2) in a murine tumor. Radiat Res 168:308-15 |
| Bratasz, Anna; Pandian, Ramasamy P; Deng, Yuanmu et al. (2007) In vivo imaging of changes in tumor oxygenation during growth and after treatment. Magn Reson Med 57:950-9 |
| Bratasz, Anna; Kulkarni, Aditi C; Kuppusamy, Periannan (2007) A highly sensitive biocompatible spin probe for imaging of oxygen concentration in tissues. Biophys J 92:2918-25 |
| Bratasz, Anna; Pandian, Ramasamy P; Ilangovan, Govindasamy et al. (2006) Monitoring oxygenation during the growth of a transplanted tumor. Adv Exp Med Biol 578:375-80 |
| Bratasz, Anna; Weir, Nathan M; Parinandi, Narasimham L et al. (2006) Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin. Proc Natl Acad Sci U S A 103:3914-9 |
| Ilangovan, Govindasamy; Bratasz, Anna; Kuppusamy, Periannan (2005) Non-invasive measurement of tumor oxygenation using embedded microparticulate EPR spin probe. Adv Exp Med Biol 566:67-73 |
| Kuppusamy, Periannan (2004) EPR spectroscopy in biology and medicine. Antioxid Redox Signal 6:583-5 |
| Kutala, Vijay Kumar; Parinandi, Narasimham L; Zweier, Jay L et al. (2004) Reaction of superoxide with trityl radical: implications for the determination of superoxide by spectrophotometry. Arch Biochem Biophys 424:81-8 |
| Ilangovan, Govindasamy; Osinbowale, Sola; Bratasz, Anna et al. (2004) Heat shock regulates the respiration of cardiac H9c2 cells through upregulation of nitric oxide synthase. Am J Physiol Cell Physiol 287:C1472-81 |
| Ilangovan, Govindasamy; Liebgott, Thibaut; Kutala, Vijay Kumar et al. (2004) EPR oximetry in the beating heart: myocardial oxygen consumption rate as an index of postischemic recovery. Magn Reson Med 51:835-42 |
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