Increased cellular proliferation is an integral part of the
cancer phenotype. Several in vitro assays have been developed to measure the rate of
tumor growth, but these require biopsies, which are particularly difficult to obtain over time and in different areas of the body in patients with multiple metastatic lesions. Most of the effort to develop imaging methods to noninvasively measure the rate of
tumor cell proliferation has focused on the use of PET in conjunction with tracers for the
thymidine salvage pathway of
DNA synthesis, because
thymidine contains the only
pyrimidine or
purine base that is unique to
DNA. Imaging with 11C-thymidine has been tested for detecting
tumors and tracking their response to
therapy in animals and patients. Its major limitations are the short half-life of 11C and the rapid catabolism of
thymidine after injection. These limitations led to the development of analogs that are resistant to degradation and can be labeled with
radionuclides more conducive to routine clinical use, such as 18F. At this point, the
thymidine analogs that have been studied the most are
3'-deoxy-3'-fluorothymidine (FLT) and 1-(2'-deoxy-2'-fluoro-1-beta-d-arabinofuranosyl)-thymine (
FMAU). Both are resistant to degradation and track the
DNA synthesis pathway. FLT is phosphorylated by
thymidine kinase 1, thus being retained in proliferating cells. It is incorporated by the normal proliferating marrow and is glucuronidated in the liver.
FMAU can be incorporated into
DNA after phosphorylation but shows less marrow uptake. It shows high uptake in the normal heart, kidneys, and liver, in part because of the role of mitochondrial
thymidine kinase 2. Early clinical data for
18F-FLT demonstrated that its uptake correlates well with in vitro measures of proliferation. Although
18F-FLT can be used to detect
tumors, its
tumor-to-normal tissue contrast is generally lower than that of
18F-FDG in most
cancers outside the brain. The most promising use for
thymidine and its analogs is in monitoring
tumor treatment response, as demonstrated in animal studies and pilot human trials. Further work is needed to determine the optimal tracer(s) and timing of imaging
after treatment.