PMID- 12084461
OWN - NLM
STAT- MEDLINE
DCOM- 20020823
LR  - 20190610
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1587
IP  - 2-3
DP  - 2002 Jul 18
TI  - Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism.
PG  - 194-205
AB  - Thymidylate synthase (TS) is a key enzyme in the de novo synthesis of 
      2'-deoxythymidine-5'-monophosphate (dTMP) from 2'-deoxyuridine-5'-monophosphate 
      (dUMP), for which 5,10-methylene-tetrahydrofolate (CH(2)-THF) is the methyl 
      donor. TS is an important target for chemotherapy; it is inhibited by folate and 
      nucleotide analogs, such as by 5-fluoro-dUMP (FdUMP), the active metabolite of 
      5-fluorouracil (5FU). FdUMP forms a relatively stable ternary complex with TS and 
      CH(2)THF, which is further stabilized by leucovorin (LV). 5FU treatment can 
      induce TS expression, which might bypass dTMP depletion. An improved efficacy of 
      5FU might be achieved by increasing and prolonging TS inhibition, a prevention of 
      dissociation of the ternary complex, and prevention of TS induction. In a panel 
      of 17 colon cancer cells, including several variants with acquired resistance to 
      5FU, sensitivity was related to TS levels, but exclusion of the resistant 
      variants abolished this relation. For antifolates, polyglutamylation was more 
      important than the intrinsic TS level. Cells with low p53 levels were more 
      sensitive to 5FU and the antifolate raltitrexed (RTX) than cells with high, 
      mutated p53. Free TS protein down-regulates its own translation, but its 
      transcription is regulated by E2F, a cell cycle checkpoint regulator. Together, 
      this results in low TS levels in stationary phase cells. Although cells with a 
      low TS might theoretically be more sensitive to 5FU, the low proliferation rate 
      prevents induction of DNA damage and 5FU toxicity. TS levels were not related to 
      polymorphisms of the TS promoter. Treatment with 5FU or RTX rapidly induced TS 
      levels two- to five-fold. In animal models, 5FU treatment resulted in TS 
      inhibition followed by a two- to three-fold TS induction. Both LV and a high dose 
      of 5FU not only enhanced TS inhibition, but also prevented TS induction and 
      increased the antitumor effect. In patients, TS levels as determined by enzyme 
      activity assays, immunohistochemistry and mRNA expression, were related to a 
      response to 5FU. 5FU treatment initially decreased TS levels, but this was 
      followed by an induction, as seen with an increased ratio of TS protein over 
      TS-mRNA. The clear retrospective relation between TS levels and response now 
      forms the basis for a prospective study, in which TS levels are measured before 
      treatment in order to determine the treatment protocol.
FAU - Peters, G J
AU  - Peters GJ
AD  - Department of Medical Oncology, VU University Medical Center, P.O. Box 7057, 1007 
      MB, Amsterdam, The Netherlands. gj.peters@vumc.nl
FAU - Backus, H H J
AU  - Backus HH
FAU - Freemantle, S
AU  - Freemantle S
FAU - van Triest, B
AU  - van Triest B
FAU - Codacci-Pisanelli, G
AU  - Codacci-Pisanelli G
FAU - van der Wilt, C L
AU  - van der Wilt CL
FAU - Smid, K
AU  - Smid K
FAU - Lunec, J
AU  - Lunec J
FAU - Calvert, A H
AU  - Calvert AH
FAU - Marsh, S
AU  - Marsh S
FAU - McLeod, H L
AU  - McLeod HL
FAU - Bloemena, E
AU  - Bloemena E
FAU - Meijer, S
AU  - Meijer S
FAU - Jansen, G
AU  - Jansen G
FAU - van Groeningen, C J
AU  - van Groeningen CJ
FAU - Pinedo, H M
AU  - Pinedo HM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Folic Acid Antagonists)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Animals
MH  - Antimetabolites, Antineoplastic/metabolism/pharmacology
MH  - Drug Resistance, Neoplasm/physiology
MH  - Enzyme Induction/drug effects
MH  - Fluorouracil/metabolism/*pharmacology
MH  - Folic Acid Antagonists/pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Neoplasms/drug therapy/enzymology/genetics
MH  - Polymorphism, Genetic
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA, Neoplasm/genetics/metabolism
MH  - Thymidylate Synthase/antagonists & inhibitors/*biosynthesis/genetics
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/metabolism
RF  - 76
EDAT- 2002/06/27 10:00
MHDA- 2002/08/24 10:01
CRDT- 2002/06/27 10:00
PHST- 2002/06/27 10:00 [pubmed]
PHST- 2002/08/24 10:01 [medline]
PHST- 2002/06/27 10:00 [entrez]
AID - S0925443902000820 [pii]
AID - 10.1016/s0925-4439(02)00082-0 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2002 Jul 18;1587(2-3):194-205. doi: 
      10.1016/s0925-4439(02)00082-0.