A novel polypyrimidine antitumor agent FdUMP[10] induces thymineless death with topoisomerase I-DNA complexes.
FdUMP[10], a 10mer of 5-fluoro-2'-deoxyuridine 5'-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. FdUMP[10] exhibits more potent antiproliferative activity than FdUMP or 5-fluoro-2'-deoxyuridine (FdU) and is markedly more active than FU. Camptothecin-resistant P388/CPT45 cells lacking Top1 are cross-resistant to FdUMP[10] as well as to FdUMP, FdU, and the thymidylate synthase inhibitor raltitrexed (Tomudex). FdUMP[10] induces DNA single-strand breaks and cellular Top1-DNA complexes. Such complexes are also observed in response to FdUMP, FdU, raltitrexed, and FU. The FdUMP[10]-induced Top1-DNA complexes are not inhibited by the caspase inhibitor z-VAD-fmk and form independently of apoptotic DNA fragmentation, indicating that they do not correspond to apoptotic Top1-DNA complexes. In biochemical assay, Top1 is directly trapped at uracil and FdU misincorporation sites. We propose that FdUMP[10] damages DNA by trapping Top1 at uracil and FdU misincorporation sites resulting from thymidylate synthase inhibition and thymine depletion.
Liao
Zhi-Yong
ZY
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland 20892-4255, USA.
Sordet
Olivier
O
Zhang
Hong-Liang
HL
Kohlhagen
Glenda
G
Antony
Smitha
S
Gmeiner
William H
WH
Pommier
Yves
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D011799:Quinazolines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013936:Thymidine / Q000172:deficiency / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; C435305:FdUMP(10); D011799:Quinazolines; D013876:Thiophenes; D059004:Topoisomerase I Inhibitors; D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase; D004264:DNA Topoisomerases, Type I; C068874:raltitrexed; D005472:Fluorouracil; D013936:Thymidine; D002166:Camptothecin