Cytotoxicity and In Vivo Tolerance of FdUMP[10]: A Novel Pro-Drug of the TS Inhibitory Nucleotide FdUMP

Abstract

The cytotoxicity of the 10mer ODN FdUMP[10] towards human colorectal tumor cells was evaluated using a clonogenic assay. FdUMP[10] was more than 100-fold more active than 5-FU at inhibiting colony formation of H630 cells. FdUMP[10] was also evaluated for cytotoxicity in the NCI 60 cell line screen, and showed markedly improved activity relative to 5-FU against numerous tumor cell lines. The in-vivo tolerance of FdUMP[10] is more than three-fold greater per mole fluorinated pyrimidine, than 5-FU.

A Novel Polypyrimidine Antitumor Agent FdUMP[10] Induces Thymineless Death with Topoisomerase I-DNA Complexes

“…In this report, we show high COMPARE correlation between FdUMP [10] and several camptothecin derivatives, cross-resistance of Top1-deficient cells to FdUMP [10], FdUMP, 5-fluoro-2V -deoxyuridine (FdU), and raltitrexed, and induction of Top1-DNA cleavage complexes in mouse and human cancer cells treated with FdUMP [10], FdUMP, FdU, and raltitrexed. We also show induction of Top1 cleavage complexes by FdU incorporation in DNA oligonucleotides.…”

“…FdUMP [10] is 338-fold more potent than FU at inhibiting cell proliferation in the National Cancer Institute (NCI) 60 cell line screen (11). Unexpectedly, COMPARE analysis showed that the FdUMP [10] activity profile clearly differed from FU but was most closely correlated with camptothecins. Because camptothecin and its derivatives selectively trap topoisomerase I (Top1; refs.…”

“…Because camptothecin and its derivatives selectively trap topoisomerase I (Top1; refs. 12,13), in this report, we studied the possible relationships between Top1 inhibition and the cellular mechanisms of action of FdUMP [10].…”

“…We also show induction of Top1 cleavage complexes by FdU incorporation in DNA oligonucleotides. A model is presented to explain Top1 trapping by FdUMP [10] treatment and thymidine depletion.…”

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AbstractFdUMP [10], a 10mer of 5-fluoro-2V -deoxyuridine 5V -monophosphate (FdUMP), the thymidylate synthase inhibitory metabolite of 5-fluorouracil (FU), is most closely correlated with the DNA topoisomerase I (Top1) inhibitor camptothecin in the National Cancer Institute COMPARE analysis, but not with FU.

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