The main objective of this project is to develop and evaluate the use of multiple-quantum-filtered (MQF) 23Na magnetic resonance (MR) spectroscopy (MRS) and imaging (MRI) for measuring compartmental Na+ in experimental tumors so that the techniques may eventually be applied clinically. The central hypothesis in this project is that MQF 23Na MR techniques can provide completely noninvasive methods for monitoring and imaging abnormalities in transmembrane sodium gradients in tumors. The experiments outlined in the proposal will also provide information about the physiological role of the transmembrane sodium gradient and its relationship with cellular energy metabolism and pHi during untreated growth, sensitization of tumors to therapy and therapy. At least two NMR methods have been proposed to distinguish between intra- and extracellular sodium (Nai+ and Nae+), the use of paramagnetic shift reagents (SR) and MQF techniques. We introduced the in vivo SR, TmDOTP5-, which produces resolved Nai+ and Nae+ resonance in tumors and other tissues with minimal toxicity to the animal. However, an SR safe for use in humans is not yet available. Our preliminary data shows that although, some Nae+ contributes to the MQF 23Na signal in the subcutaneously implanted 9L glioma, this signal does not change during ischemia. If this is true under more general conditions, then MQF 23Na MR techniques can provide completely noninvasive methods for monitoring and imaging changes in Nai+ in tumors. The first goal of this study is to determine whether MQF 23Na MRS can be used to measure changes in Nai+ during more subtle acute manipulations. The effects of manipulating the tumor energy metabolism and ion exchange mechanisms will be studied. The chosen manipulations are used for sensitizing tumor to therapy. Our second goal is to evaluate the use of MQF 23Na MRS for monitoring changes in Nai+ during chronic physiological changes. For this purpose, effects of untreated tumor growth, radiotherapy and chemotherapy will be studied and the efficacy of MQF 23Na MRS/MRI for detecting tumor response to chemotherapy by a broad range of antineoplastic agents employed in clinical cancer chemotherapy will be investigated in RIF-1 and MCF-7 tumor models. The development of proposed 23Na MR techniques will provide methods for monitoring and imaging Nai+ that may prove useful in experimental studies of tumors and clinical management of cancer. In addition, the proposed research will enhance the understanding of sodium physiology in tumors, which may prove useful for designing more effective cancer treatment, and for predicting and monitoring response to therapy.
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