A challenge to oncologists in the future is to individualize each and every tumor by tailoring treatments to those which are the most effective. Ideally, these choices must be made at the earliest point possible following the beginning of therapy. Monitoring therapeutic response is best done non-invasively, and can include molecular biological assays as well as radiological methods. A potentially powerful method to non-invasively monitor treatment response is Diffusion Magnetic Resonance Imaging (DWI). Diffusion MRI can accurately and quantitatively determine the apparent diffusion coefficient of tissue water (ADCW). Studies in experimental animals have shown that ADCW in tumors increases in cells undergoing successful chemotherapy. The observation of a increases ADCW is potentially useful for clinical evaluation of chemotherapeutic response and this will be investigated in a companion R2 I proposal. However, a deeper understanding of the relationship between the diffusion properties of tumor water and the metabolic state of cells would increase its utility in assessing the state of tumor tissue, predicting outcome and designing therapies. In this proposal, we will examine the mechanisms underlining the ADCW changes using well-defined in vitro and in vivo systems. The two main hypothesis behind the proposed research plan are that 1) The ADCW in tumors is a surrogate measure of cell volume, and 2) The changes in ADCW in response to chemotherapy are a marker for apoptosis. This proposal represents a thorough evaluation of the relationship between ADCW, cell volume and response to chemotherapy. An well-characterized in vitro bioreactor system will provide the necessary control over system parameters to understand the basic mechanisms responsible for the observed changes in vivo.
