Suicide prodrugs activated by thymidylate synthase: Rationale for treatment and noninvasive imaging of tumors with deoxyuridine analogues

Citation
Jm. Collins et al., Suicide prodrugs activated by thymidylate synthase: Rationale for treatment and noninvasive imaging of tumors with deoxyuridine analogues, CLIN CANC R, 5(8), 1999, pp. 1976-1981
Citations number
16
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
1078-0432 → ACNP
Volume
5
Issue
8
Year of publication
1999
Pages
1976 - 1981
Database
ISI
SICI code
1078-0432(199908)5:8<1976:SPABTS>2.0.ZU;2-X
Abstract
Most tumors are resistant to therapy by thymidylate synthase (TS) inhibitor s 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 (deox yuridine analogues) to more toxic species (thymidine analogues). Tumors wit h high levels of TS could be particularly sensitive to deoxyuridine analogu es because they would be more efficient in producing the toxic methylated s pecies. Furthermore. the accumulation of methylated species within tumors c ould be visualized externally if a tracer dose of the deoxyuridine analogue was tagged with an isotope, preferably a positron emitter, such as F-18. H igher accumulation of isotope indicates higher activity of TS and lower sen sitivity of the tumor to TS inhibitors, but perhaps more sensitivity to the rapy 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 subsequ ently incorporated into cellular DNA, Among different cell lines, FAU produ ced 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 minimall y decreased. As the first demonstration that cells with high levels of TS a ctivity 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 [F-18]FAU and that this phenotypic information could guide patient therapy .