Gene expression in colorectal cancer and in vitro chemosensitivity to 5‐fluorouracil: A study of 88 surgical specimens

Abstract

To predict the sensitivity of colorectal cancer to 5-fluorouracil (5-FU), we compared the gene expression of surgically obtained colorectal cancer specimens with chemosensitivity to 5-FU as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. Eighty-eight patients with advanced and/or metastatic colorectal cancer provided written informed consent and entered the trial from September 2000 to October 2001. Fresh surgical specimens were used for the MTT assay, and sensitivity to 5-FU was evaluated at a cutoff concentration of 50 µ µ µ µg/ml and 48-h incubation time. Frozen samples were stored at − − − −80°C until mRNA analysis of thymidylate synthetase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), esnucleoside transporter (NT), and E2F1 by real-time RT-PCR. The correlations between the variables were analyzed, and the predictive value of these mRNAs was assessed statistically using a receiver operating characteristic (ROC) curve. NT and DPD, TP and DPD, and TP and NT mRNA expression levels correlated significantly, while TS and E2F1 showed no correlations. High NT expression was associated with low sensitivity to 5-FU (P < < < <0.013), as were high DPD and E2F1 expression (P < < < <0.022 for both). High TP mRNA expression correlated with low sensitivity to 5-FU (P < olorectal cancer is a major cause of cancer-related mortality. In attempts to improve the outcome of this disease, clinical trials of adjuvant systemic therapy have been performed. The combination of 5-fluorouracil (5-FU) and leucovorin (LV) has been the "standard" therapy for patients with colorectal cancer for over a decade. National Surgical Adjuvant Breast and Bowel Project trials that compared different adjuvant chemotherapy regimens with no adjuvant treatment have reported the relative efficacy of adjuvant chemotherapy in terms of Dukes' staging. Overall, disease-free, and recurrencefree survivals were improved for Dukes' C patients in all four trials.<1-3) Recently, great efforts have been made to improve the efficacy of 5-FU. The third-generation oral 5-FU prodrugs, including orzel, S-1, and capecitabine, may eventually replace infusional 5-FU therapy and improve patients' quality of life by allowing outpatient therapy. Novel combinations of 5-FU or its analogs with agents that have different mechanisms of action (e.g., oxaliplatin, irinotecan) could provide important new opportunities for improving the outlook for patients with colorectal cancer. 4)When a meta-analysis was conducted on nine randomized clinical trials that compared 5-FU with 5-FU plus intravenous LV in patients with advanced colorectal cancer, 5-FU plus LV showed a highly significant benefit over 5-FU alone in terms of tumor response rate, but this increase in response did not result in a discernable improvement in overall survival. However, a large number of patients did not respond to treatment in both groups.5) We reported previously that the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (M...

Overexpression of the Orotate Phosphoribosyl-Transferase Gene Enhances the Effect of 5-Fluorouracil on Gastric Cancer Cell Lines

“…Enhanced activity of DPD is known to endow tumor cells with resistance to 5-FU in vitro and in clinical studies [22,23,24,25]. Using 88 surgical specimens, Yoshinare et al [22] demonstrated that high DPD mRNA expression is associated with low sensitivity to FU-based chemotherapy in metastatic colorectal cancer patients. Moreover, the activation and regulation of the DPD gene are also of great interest in predicting the efficacy of 5-FU.…”

Synergistic effects of docetaxel and S‐1 by modulating the expression of metabolic enzymes of 5‐fluorouracil in human gastric cancer cell lines

“…[32][33][34][35] Low levels of DPD mRNA expression has also been associated with a low sensitivity to 5-FU and has also been correlated with a low sensitivity to fluoropyrimidine-based chemotherapy in colorectal cancer patients. [36][37][38][39] TS as well as DPD is an enzyme that plays key roles in 5-FU resistance in carcinoma cells. High intratumoral TS mRNA levels are believed to confer 5-FU resistance due to resulting inefficient TS inhibition.…”

Identification of genes conferring resistance to 5-fluorouracil

“…5-FU is converted into its inactive metabolite fluoro-5,6-dihydrouracil (FUH 2 ) by dihydropyrimidine dehydrogenase (DPYD) (37). TS and DPYD gene expression and/or activity are major determinants of the efficacy of 5-FU (38,39).…”