Suicide prodrugs activated by thymidylate synthase: rationale for treatment and noninvasive imaging of tumors with deoxyuridine analogues.
Most tumors are resistant to therapy by thymidylate synthase (TS) inhibitors due to their high levels of TS. Instead of inhibiting TS, we hypothesized that it was possible to use this enzyme to activate suicide prodrugs (deoxyuridine analogues) to more toxic species (thymidine analogues). Tumors with high levels of TS could be particularly sensitive to deoxyuridine analogues because they would be more efficient in producing the toxic methylated species. Furthermore, the accumulation of methylated species within tumors could be visualized externally if a tracer dose of the deoxyuridine analogue was tagged with an isotope, preferably a positron emitter, such as 18F. Higher accumulation of isotope indicates higher activity of TS and lower sensitivity of the tumor to TS inhibitors, but perhaps more sensitivity to therapy with deoxyuridine analogues as suicide prodrugs. 2'-F-ara-deoxyuridine (FAU) was used as a prototype to demonstrate these concepts experimentally. FAU readily entered cells and was phosphorylated, methylated, and subsequently incorporated into cellular DNA. Among different cell lines, FAU produced varying degrees of growth inhibition. Greater DNA incorporation (e.g., for CEM and U-937 cells) was reflected as increased toxicity. FAU produced less DNA incorporation in Raji or L1210 cells, and growth rate was minimally decreased. As the first demonstration that cells with high levels of TS activity can be more vulnerable to therapy than cells with low TS activity, this preliminary work suggests a new therapeutic approach for common human tumors that were previously resistant. Furthermore, it appears that the TS activity of tumors could be noninvasively imaged in situ by tracer doses of [18F]FAU and that this phenotypic information could guide patient therapy.
Collins
J M
JM
Laboratory of Clinical Pharmacology, Food and Drug Administration, Rockville, Maryland 20850, USA. collinsj@cder.fda.gov
Klecker
R W
RW
Katki
A G
AG
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D005467:Floxuridine / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D006801:Humans; D008745:Methylation; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011355:Prodrugs / Q000378:metabolism* / Q000493:pharmacokinetics; D013940:Thymidylate Synthase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D005462:Fluorine Radioisotopes; D011355:Prodrugs; D005467:Floxuridine; D001086:Arabinofuranosyluracil; C037289:2'fluoro-2'-deoxyuridine; D004247:DNA; D013940:Thymidylate Synthase; C034935:clevudine