PMID- 15161716
OWN - NLM
STAT- MEDLINE
DCOM- 20041210
LR  - 20171116
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 10
IP  - 10
DP  - 2004 May 15
TI  - The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in 
      response to antimetabolites.
PG  - 3562-71
AB  - Fas (CD95/Apo-1) is a member of the tumor necrosis factor receptor family. 
      Receptor binding results in activation of caspase 8, leading to activation of 
      proapoptotic downstream molecules. We found that expression of Fas was 
      up-regulated >10-fold in MCF-7 breast and HCT116 and RKO colon cancer cell lines 
      after treatment with IC(60) doses of 5-fluorouracil (5-FU) and raltitrexed (RTX). 
      Combined treatment with the agonistic Fas antibody CH-11 and either 5-FU or RTX 
      resulted in a highly synergistic induction of apoptosis in these cell lines. 
      Similar results were obtained for another antifolate, Alimta. Induction of 
      thymidylate synthase expression inhibited Fas induction in response to RTX and 
      Alimta, but not in response to 5-FU. Furthermore, thymidylate synthase induction 
      abrogated the synergy between CH-11 and both antifolates but had no effect on the 
      synergistic interaction between 5-FU and CH-11. Inactivation of p53 in MCF-7 and 
      HCT116 cell lines blocked 5-FU- and antifolate-mediated up-regulation of Fas. 
      Furthermore, Fas was not up-regulated in response to 5-FU or antifolates in the 
      p53-mutant H630 colon cancer cell line. Lack of Fas up-regulation in the p53-null 
      and -mutant lines abolished the synergistic interaction between 5-FU and CH-11. 
      Interestingly, synergy was still observed between the antifolates and CH-11 in 
      the p53-null HCT116 and p53-mutant H630 cell lines, although this was 
      significantly reduced compared with the p53 wild-type cell lines. Our results 
      indicate that Fas is an important mediator of apoptosis in response to both 5-FU 
      and antifolates.
FAU - Longley, Daniel Broderick
AU  - Longley DB
AD  - Department of Oncology, Cancer Research Centre, Queen's University Belfast, 
      Belfast, Northern Ireland.
FAU - Allen, Wendy Louise
AU  - Allen WL
FAU - McDermott, Ultan
AU  - McDermott U
FAU - Wilson, Timothy Richard
AU  - Wilson TR
FAU - Latif, Tariq
AU  - Latif T
FAU - Boyer, John
AU  - Boyer J
FAU - Lynch, Maria
AU  - Lynch M
FAU - Johnston, Patrick Gerard
AU  - Johnston PG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibodies)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antimetabolites)
RN  - 0 (CH-11 anti-fas antibody, human)
RN  - 0 (Folic Acid Antagonists)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (fas Receptor)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - F8VB5M810T (Tetracycline)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Antibodies/pharmacology
MH  - Antibodies, Monoclonal/chemistry
MH  - Antimetabolites/*pharmacology
MH  - *Apoptosis
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Dose-Response Relationship, Drug
MH  - Flow Cytometry
MH  - Fluorouracil/pharmacology
MH  - Folic Acid Antagonists/metabolism/pharmacology
MH  - Genes, p53
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Mutation
MH  - Oligonucleotide Array Sequence Analysis
MH  - Protein Binding
MH  - Signal Transduction
MH  - Tetracycline/pharmacology
MH  - Thymidylate Synthase/*physiology
MH  - Transgenes
MH  - Tumor Suppressor Protein p53/metabolism/*physiology
MH  - Up-Regulation
MH  - fas Receptor/*metabolism
EDAT- 2004/05/27 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/05/27 05:00
PHST- 2004/05/27 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/05/27 05:00 [entrez]
AID - 10/10/3562 [pii]
AID - 10.1158/1078-0432.CCR-03-0532 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2004 May 15;10(10):3562-71. doi: 10.1158/1078-0432.CCR-03-0532.