5-fluorouracil (5-FU) is a common chemotherapeutical drug. It exerts its antitumor effect through competitive thymidylate synthase (TS) inhibition. Thymidylate synthase (TS) catalyses deoxyuridine-5-monophosphate (dUMP) to 2-deoxythymydine-5-monophosphate (dTMP). It is the only de novo source of thymidylate, an essential precursor of DNA biosynthesis. In the 5-untranslated region of TS gene, there a unique tandem repeated sequence. There are three predominant genotypes of TS: (1) Homozygous with two tandem repeats (2R/2R); (2) homozygous with three tandem repeats (3R/3R); (3) heterozygous with both alleles (2R/3R). It was reported that TS genes with the triple repeats have higher expression activity than those with double repeats in vitro and in vivo.
The critical role of TS in nucleotide metabolism has made it an important target for cancer chemotherapy. Intratumoral TS protein expression before the chemoradiation treatment has been observed to inversely correlate with the response to 5-FU chemotherapy. Patients with low TS levels have better clinical outcome than those with high TS levels. Detecting the intratumoral TS levels is important for patients who are going to receive 5-FU-based chemotherapy, as these can be used to forecast the efficacy of chemotherapy. However, the classical assay for TS-activity determination (high-performance liquid chromatography with output monitored by radioactive flow detector) is tedious and expensive. A simple way to detect the TS levels is necessary. A research article to be published on January 28, 2008 in the World Journal of Gastroenterology addresses this question.
Immunoreactivity score (IRS) is a semiquantitative analysis for detecting the immunostaining results. Dr.Wei-Xing Wang and his colleagues used monoclonal antibody TS106 to detect the TS protein in the paraffin-embedded specimens. The samples came from 68 colonic neoplasms of Han Chinese patients. At the same time, the team also observed the link between TS genotype and IRS of TS. Three genotypes of TS were found: 2R/2R (n = 6), 2R/3R (n = 22) and 3R/3R (n = 40). Patients who were homozygous for triple-repeated (3R/3R) sequences showed significantly higher IRS of TS than patients who were homozygous for double-repeated (2R/2R) sequences or heterozygous patients (2R/3R), but no statistical significance of IRS in cancer tissues was observed between 2R/3R genotype and 2R/2R genotype. These results suggested TS genotype may be a genetic factor which can be used to predict the patients response to 5-FU-based chemotherapy. The data might offer an advantage for selection of Chinese cancer patients to receive fluoropyrimidines treatment.
|Contact: Jing Zhu|
World Journal of Gastroenterology