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Title: Low cytosine triphosphate synthase 2 expression renders resistance to 5-fluorouracil in colorectal cancer
Authors: Tan, W.L.
Bhattacharya, B. 
Loh, M. 
Balasubramanian, I. 
Akram, M.
Dong, D. 
Wong, L. 
Thakkar, B. 
Salto-Tellez, M. 
Soo, R.A. 
Fichtner, I.
Iacopetta, B.
Soong, R. 
Keywords: 5-fluorouracil
Cytidine triphosphate synthase
Drug resistance
Pathway analysis
Issue Date: 2011
Citation: Tan, W.L., Bhattacharya, B., Loh, M., Balasubramanian, I., Akram, M., Dong, D., Wong, L., Thakkar, B., Salto-Tellez, M., Soo, R.A., Fichtner, I., Iacopetta, B., Soong, R. (2011). Low cytosine triphosphate synthase 2 expression renders resistance to 5-fluorouracil in colorectal cancer. Cancer Biology and Therapy 11 (6) : 599-608. ScholarBank@NUS Repository.
Abstract: Understanding the determinants of resistance of 5-fluorouracil (5FU) is of significant value to optimizing administration of the drug, and introducing novel agents and treatment strategies. Here, the expression of 92 genes involved in 5FU transport, metabolism, co-factor (folate) metabolism and downstream effects was measured by real-time PCR low density arrays in 14 patient-derived colorectal cancer xenografts characterized for 5FU resistance. Candidate gene function was tested by siRNA and uridine modulation, and immunoblotting, apoptosis and cell cycle analysis. Predictive significance was tested by immunohistochemistry of tumors from 125 stage III colorectal cancer patients treated with and without 5FU. Of 8 genes significantly differentially expressed between 5FU sensitive and resistant xenograft tumors, CTPS2 was the gene with the highest probability of differential expression (p = 0.008). Reduction of CTPS2 expression by siRNA increased the resistance of colorectal cancer cell lines DLD1 and LS174T to 5FU and its analog, FUDR. CTPS2 siRNA significantly reduced cell S-phase accumulation and apoptosis following 5FU treatment. Exposure of cells to uridine, a precursor to the CTPS2 substrate uridine triphosphate, also increased 5FU resistance. Patients with low CTPS2 did not gain a survival benefit from 5FU treatment (p = 0.072), while those with high expression did (p = 0.003). Low CTPS2 expression may be a rationally-based determinant of 5FU resistance. © 2011 Landes Bioscience.
Source Title: Cancer Biology and Therapy
ISSN: 15384047
DOI: 10.4161/cbt.11.6.14670
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