TY - JOUR
T1 - A proposed clinical test for monitoring fluoropyrimidine therapy
T2 - Detection and stability of thymidylate synthase ternary complexes
AU - Brody, Jonathan R.
AU - Gallmeier, Eike
AU - Yoshimura, Kiyoshi
AU - Hucl, Tomas
AU - Kulesza, Peter
AU - Canto, Marcia I.
AU - Hruban, Ralph H.
AU - Schulick, Richard D.
AU - Kern, Scott E.
PY - 2006/8
Y1 - 2006/8
N2 - 5-fluorouracil forms classic (covalent, ternary) complexes consisting of thymidylate synthase, fluoro-deoxyuridine monophosphate, and 5,10-methylene tetrahydrofolate. Despite a high pharmacologic interest in the classic complexes formed in cells treated with fluorouracil anticancer agents, the in vivo stability of the complexes and the possible interference in complex formation by other coadministered compounds have not been adequately described. We visualized classic complexes unaccompanied by unbound thymidylate synthase, inferring complete enzymatic inhibition, in 5-fluorouracil-treated S. cerevisiae and cancer cells in vitro and in murine tumors in vivo treated with 5-fluorouracil. Classic complexes persisted 13 days in cancer cells after a pulse of 5-fluorouracil. Classic complexes were reduced to absent in cancer cells in which the older antifolates methotrexate and aminopterin, or the modern antifolates pemetrexed and tomudex, were coadministered with 5-fluorouracil. Classic complexes were, however, detected when an alternate drug, 5-fluorodeoxyuridine, was administered with methotrexate. We visualized classic complexes at fifteen minutes to seven days after an acute single dose of 5-fluorouracil in mouse tumor models, in tumors and normal tissues. Using the same assay, we detected unbound thymidylate synthase in untreated human tissues, supporting the future use of this assay in evaluating the most appropriate dose of fluoropyrimidine and coadministered agents in clinical settings.
AB - 5-fluorouracil forms classic (covalent, ternary) complexes consisting of thymidylate synthase, fluoro-deoxyuridine monophosphate, and 5,10-methylene tetrahydrofolate. Despite a high pharmacologic interest in the classic complexes formed in cells treated with fluorouracil anticancer agents, the in vivo stability of the complexes and the possible interference in complex formation by other coadministered compounds have not been adequately described. We visualized classic complexes unaccompanied by unbound thymidylate synthase, inferring complete enzymatic inhibition, in 5-fluorouracil-treated S. cerevisiae and cancer cells in vitro and in murine tumors in vivo treated with 5-fluorouracil. Classic complexes persisted 13 days in cancer cells after a pulse of 5-fluorouracil. Classic complexes were reduced to absent in cancer cells in which the older antifolates methotrexate and aminopterin, or the modern antifolates pemetrexed and tomudex, were coadministered with 5-fluorouracil. Classic complexes were, however, detected when an alternate drug, 5-fluorodeoxyuridine, was administered with methotrexate. We visualized classic complexes at fifteen minutes to seven days after an acute single dose of 5-fluorouracil in mouse tumor models, in tumors and normal tissues. Using the same assay, we detected unbound thymidylate synthase in untreated human tissues, supporting the future use of this assay in evaluating the most appropriate dose of fluoropyrimidine and coadministered agents in clinical settings.
KW - 5-fluorouracil
KW - Antifolates
KW - Leucovorin
KW - Ternary complex
KW - Thymidylate synthase
UR - http://www.scopus.com/inward/record.url?scp=33751093171&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33751093171&partnerID=8YFLogxK
U2 - 10.4161/cbt.5.8.2976
DO - 10.4161/cbt.5.8.2976
M3 - Article
C2 - 16855390
AN - SCOPUS:33751093171
SN - 1538-4047
VL - 5
SP - 923
EP - 927
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 8
ER -