Relationships between the expression of thymidylate synthase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase and cell proliferative activity and 5-fluorouracil sensitivity in colorectal carcinoma

Abstract

The results suggest that OPRT activity can predict sensitivity to 5-FU, and high OPRT activity may cause good 5-FU sensitivity in cancers with high cell proliferative activity.

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

“…Previous clinical studies also revealed the positive expression and activity of OPRT to be associated with the responsiveness to 5-FU in a variety of human cancers, including colorectal cancers (Isshi et al, 2002;Fujii et al, 2003;Ichikawa et al, 2003a;Matsuyama et al, 2006) and bladder carcinomas (Mizutani et al, 2004). However, these studies were performed using relatively small number of patients, and then were evaluated by biochemical assays for OPRT enzyme activity or reverse transcriptional PCR (RT -PCR) assays for OPRT gene expression.…”

“…Clinical studies have reported their sensitivity to be associated with the target molecule TS (Rustum et al, 1997), fluoropyrimidinemetabolising enzymes such as orotate phosphoribosyltransferase (OPRT) (Peters et al, 1986), and the 5-FU-catabolitic enzyme such as dihydropyrimidine dehydrogenase (DPD) (Beck et al, 1994). However, there were only a few clinical studies on the simultaneous evaluations of these biomarkers to evaluate 5-FU sensitivity (Isshi et al, 2002;Fujii et al, 2003;Ichikawa et al, 2003a).…”

Genetic factors influencing Pyrimidine-antagonist chemotherapy

“…High OPRT activity was associated with good in vitro sensitivity to 5-FU, measured by Collagen Gel Droplet Embedded Culture Drug Sensitivity test, Fluoresceine Diacetate Assay or Histoculture Drug Response Assay, in human colorectal cancer tissues. 68,69 Furthermore, in 37 patients treated with oral tegafur-uracil for disseminated colorectal cancer, responding tumours had higher expressions of OPRT than nonresponding tumours. 70 In the same study, there was no difference in UP mRNA between responding and nonresponding tumours.…”

“…An overview of clinical relevant studies is presented in Table 2. Most studies have been performed in colorectal cancer, 68,[88][89][90][91] some in gastric, [92][93][94] head and neck, [95][96][97] and non-small-cell lung cancer, [98][99][100] and few in breast and bladder cancer. 101,102 A number of studies have indicated that there is no strong link between DPD mRNA levels and DPD protein activity levels.…”

“…An overview of relevant clinical studies is presented in Table 4. Most studies regarding TS expression in relation to chemosensitivity have been performed in patients with disseminated colorectal cancer, 68,91,[122][123][124][125][126][127][128][129][130][131][132][133][134] some in gastric cancer 94,[135][136][137][138] and few studies in head and neck cancer, 95,96,139 non-small-cell lung cancer 99,100 pancreatic and breast cancer. 84,140,141 Several factors may account for the difficult interpretation of combined clinical data.…”