Advances in morphological imaging, particularly MRI and CT, have significantly improved tumor detection, staging and measurement of therapy response. Improvement in cancer patient management through imaging is unlikely to continue at a similar rate unless anatomical studies are augmented with an assessment of tumor biology and metabolism in vivo. Progress towards this goal has been made using positron emission tomography (PET) and an in vivo radiotracer of glucose utilization, [18F] fluodeoxyglucose (FDG). However, FDG and other radiotracers currently used in PET oncology studies are, at best, indirect measures of cell proliferation. Investigators have employed traditional methodologies for measuring DNA synthesis, such as determination of biodistribution, biochemical radioassay, and autoradiography with [3H] or [14C] TdR, as well as immunohistochemistry with bromodeoxyuridine (BUdR), in order to validate the use of [11C] TdR with PET. Among the many issues surrounding development of an in vivo method for quantitating DNA synthesis with [11C] TdR, perhaps the most cumbersome is its rapid in vivo catabolism, which complicates interpretation of PET kinetic data. We propose to specifically address this issue and hypothesize that a measurement of cell proliferation equivalent to volumetric mitotic index (MIv), i.e., the fraction of tumor volume occupied by dividing (S-phase cells) can be achieved in vivo with PET using a non-catabolized nucleoside anolog of thkymidine: 2'-fluoro-5-[11C]-methyl-1-beat-D-arabinofuranosyluracil (FMAU). The efficacy of this radiotracaer for monitoring DNA synthesis will be examined in animal tumor models and patients in comparison with MIv, as measured with BUdR and quantitative histology. Studies using [14C] FMAU confirm the absence of significant labeled catabolites in plasma, demonstrate that tumors can be well visualized with PET, and indicate that uptake into tumor and normal organs is positively correlated with MIv. We propose to test the hypothesis that measurements of cell proliferaton paralleling BUdR mitotic index can be obtained in vivo with PET and [11C]FMAU.
