PMID- 11445856
OWN - NLM
STAT- MEDLINE
DCOM- 20011004
LR  - 20190605
IS  - 1019-6439 (Print)
IS  - 1019-6439 (Linking)
VI  - 19
IP  - 2
DP  - 2001 Aug
TI  - Polymorphism in the thymidylate synthase promoter enhancer region in colorectal 
      cancer.
PG  - 383-6
AB  - Thymidylate synthase (TS) is an important target for chemotherapy drugs such as 
      5-fluorouracil and raltitrexed. Over-expression of TS has been linked to 
      chemotherapy resistance. A polymorphic tandem repeat sequence in the 5' 
      untranslated region (5'UTR) of the human TS gene (TSER) has been shown to 
      influence TS expression. The presence of a triple tandem repeat (TSER*3) 
      increases in vitro TS expression compared to a double tandem repeat (TSER*2) and 
      is associated with higher in vivo tumor TS activity. The polymorphism of this 
      promoter enhancer region has not been extensively studied in patients with cancer 
      and may represent a possible mechanism of intrinsic resistance to TS inhibitors. 
      In this study, PCR analysis of genomic DNA from 121 patients with colorectal 
      cancer demonstrated 29% of patients were homozygous for TSER*3, 16% were 
      homozygous for TSER*2 and 55% were heterozygous. In 44/45 microdissected tumors 
      the TS enhancer genotype was identical between paired samples of colorectal tumor 
      and normal tissue. In 24 patients receiving a bolus/infusion 5-fluorouracil (5FU) 
      regimen for metastatic colorectal cancer, 22% of non-responders to chemotherapy 
      were homozygous for TSER*2 compared with 40% of responders. Median survival 
      dropped from 16 months for homozygous TSER*2 to 12 months for homozygous TSER*3. 
      This is consistent with previous studies where higher TS expression was 
      associated with poor response to TS inhibitors. Prospective analysis of the 
      influence of the TS polymorphism on patient outcome is warranted.
FAU - Marsh, S
AU  - Marsh S
AD  - Department of Medicine and Therapeutics, Institute of Medical Sciences, 
      University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
FAU - McKay, J A
AU  - McKay JA
FAU - Cassidy, J
AU  - Cassidy J
FAU - McLeod, H L
AU  - McLeod HL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (DNA, Neoplasm)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
SB  - IM
MH  - Colorectal Neoplasms/*genetics/pathology
MH  - DNA, Neoplasm/chemistry/genetics
MH  - Enhancer Elements, Genetic/*genetics
MH  - Gene Frequency
MH  - Genotype
MH  - Humans
MH  - Polymorphism, Genetic
MH  - Promoter Regions, Genetic/*genetics
MH  - Tandem Repeat Sequences/genetics
MH  - Thymidylate Synthase/*genetics
EDAT- 2001/07/11 10:00
MHDA- 2001/10/05 10:01
CRDT- 2001/07/11 10:00
PHST- 2001/07/11 10:00 [pubmed]
PHST- 2001/10/05 10:01 [medline]
PHST- 2001/07/11 10:00 [entrez]
AID - 10.3892/ijo.19.2.383 [doi]
PST - ppublish
SO  - Int J Oncol. 2001 Aug;19(2):383-6. doi: 10.3892/ijo.19.2.383.