Thymidylate synthase gene variations: predictive and prognostic markers.
Since its introduction more than 50 years ago by Heidelberger et al., the fluoropyrimidine 5-fluorouracil (5-FU) has remained the mainstay of therapeutic regimens used in the treatment of colorectal cancer and other human malignancies, with single-agent response rates of 20% to 25% in advanced disease stage. Pharmacogenomics has emerged as a useful tool to address interindividual gene variations by analyzing the interplay of host and tumor genotype and drug efficacy and toxicity. Having a reliable panel of prognostic and predictive markers will be critical in selecting an individualized and tailored chemotherapy regimen based on the particular tumor and host genotype. Although conflicting results have been reported, higher thymidylate synthase (TS) protein and mRNA expression levels in tumors have generally been associated with poor clinical outcome in patients treated with 5-FU-based chemotherapy regimens. However, the cause of the variability in TS expression still remains not fully understood, although several germ-line polymorphisms seem to affect the expression of TS, some of which have been found to have an effect on prognosis and the probability of response to 5-FU-based chemotherapy. This review will provide an update on pharmacogenomic studies of TS that were aimed at elucidating their role as prognostic and predictive markers.
Lurje
Georg
G
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California, USA.
Manegold
Philipp C
PC
Ning
Yan
Y
Pohl
Alexandra
A
Zhang
Wu
W
Lenz
Heinz-Josef
HJ
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011379:Prognosis; D013940:Thymidylate Synthase / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D013940:Thymidylate Synthase; D005472:Fluorouracil