title: Targeting the de novo biosynthesis of thymidylate for the development of a PET probe for pancreatic cancer imaging.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Thushani D
authors.initials: TD
authors.lastname: Nilaweera
authors.forename: Muhammad
authors.initials: M
authors.lastname: Saeed
authors.forename: Amnon
authors.initials: A
authors.lastname: Kohen
mesh_terms: D002247:Carbon Isotopes; D005492:Folic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007553:Isotope Labeling; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011859:Radiography; D013938:Thymidine Monophosphate / Q000096:biosynthesis* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000096:biosynthesis*; D014542:Uridine Monophosphate / Q000378:metabolism
chemical_list: D002247:Carbon Isotopes; D011849:Radioactive Tracers; D013938:Thymidine Monophosphate; C032418:5,11-methenyltetrahydrohomofolate; D005492:Folic Acid; D014542:Uridine Monophosphate; D013940:Thymidylate Synthase