The development of
cancer-specific probes for imaging by positron emission tomography (PET) is gaining impetus in
cancer research and clinical oncology. One of the hallmarks of most
cancer cells is incessant DNA replication, which requires the continuous synthesis of
nucleotides.
Thymidylate synthase (TSase) is unique in this context because it is the only
enzyme in humans that is responsible for the de novo biosynthesis of the
DNA building block 2'-deoxy-thymidylate (
dTMP). TSase catalyzes the reductive methylation of 2'-deoxy-uridylate (dUMP) to
dTMP using (R)-N(5),N(10)-methylene-5,6,7,8-tetrahydrofolate (
MTHF) as a cofactor. Not surprisingly, several human
cancers overexpress TSase, which makes it a common target for
chemotherapy (e.g., 5-fluorouracil). We envisioned that [(11)C]-
MTHF might be a PET probe that could specifically label cancerous cells. Using stable radiotracer [(14)C]-
MTHF, we had initially found increased uptake by breast and
colon cancer cell lines. In the current study, we examined the uptake of this radiotracer in human
pancreatic cancer cell lines MIAPaCa-2 and PANC-1 and found predominant radiolabeling of cancerous versus normal pancreatic cells. Furthermore, uptake of the radiotracer is dependent on the intracellular level of the
folate pool, cell cycle phase, expression of
folate receptors on the cell membrane, and cotreatment with the common chemotherapeutic
drug methotrexate (MTX, which blocks the biosynthesis of endogenous
MTHF). These results point toward [(11)C]-
MTHF being used as PET probe with broad specificity and being able to control its signal through MTX co-administration.