7372

UMPS

uridine monophosphate synthetase;UMPS;uridine monophosphate synthetase

OMPdecase|OPRTase|UMP synthase|orotate phosphoribosyltransferase|orotidine 5'-phosphate decarboxylase|uridine 5'-monophosphate synthase

3q13

protein-coding

Activation of 5-fluorouracil into its nucleotides requires phosphorylation by three pathways involving orotate phosphoribosyl-transferase (OPRT), uridine phosphorylase (UP), or thymidine phosphorylase (TP). In this study, we investigated the association between gene expressions of these three enzymes and antitumour effect. Gene expressions in primary colorectal tumours were analysed by a real-time reverse transcriptional-polymerase chain reaction method in 37 patients receiving oral treatment of tegafur-uracil and leucovorin for metastatic diseases. The median values of OPRT mRNA expressions were 1.39 and 0.85 for responding tumours and nonresponding tumours, respectively, showing a statistically significant difference (P=0.0008). Responding tumours had statistically lower expressions of TP mRNA than nonresponding tumours (P=0.006). However, there was no difference in UP mRNA expression between responding and nonresponding tumours. Patients with high OPRT (>/=1.0) gene expression survived longer than those with low OPRT (<1.0) expression. Dihydropyrimidine dehydrogenase (DPD) gene expressions were measured. Responding tumours had a statistically higher OPRT/DPD ratio than the nonresponding ones (P=0.003). When the median value of the OPRT/DPD ratio was selected as the cutoff value, patients with a high OPRT/DPD ratio survived statistically longer than those with a low ratio (P=0.0014). In conclusion, both the expression of OPRT gene and the OPRT/DPD ratio might be useful as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer.

The purpose of this study was to evaluate the pattern of the expression of orotate phosphoribosyltransferase (OPRT) in several components of colorectal carcinoma (CRC). Fifty-six surgically-resected samples of CRC were subjected to immunohistochemistry with a polyclonal anti-OPRT antibody. Grading was performed independently for several components of CRC, including mucosal carcinoma lesions (n=56), infiltrative lesions (n=53), lymphovascularly invasive lesions (n=34) and metastatic lymph nodes (n=17). The expression of OPRT in mucosal carcinoma and infiltrative lesions correlated significantly only with the presence of lymphovascular invasion (p=0.0007 and <0.0001, respectively). The frequency of OPRT expression in mucosal carcinoma, infiltrative and lymphovascularly invasive lesions as well as metastatic lymph nodes was 32.1, 69.8, 88.2 and 88.8%, respectively. In addition, nuclear staining of OPRT was observed in metastatic lymph nodes and lymphovascularly invasive lesions. Our results suggest that OPRT is involved in the invasion and metastasis of CRC.

AIM: The activity of the widely used anticancer drug 5-fluorouracil (5-FU) is determined by the presence of several enzymes, including dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), and thymidylate synthase (TS). This study compared the expression levels of these enzymes between primary colorectal cancer with and without distant metastases, and examined whether these expression patterns are associated with hematogenous metastasis. MATERIALS AND METHODS: Among 40 patients with colorectal cancer, 20 had no metastasis and 20 had distant metastasis. Strong expression on immunohistochemistry was classified as positive, while weak, moderate or no expression was classified as negative. RESULTS: Positive expressions of DPD, OPRT and TS in primary colorectal cancer tissue were seen in 47.5%, 75% and 20%, respectively. However, no relationships were observed among the expressions of DPD, OPRT and TS. expressions of OPRT (p=0.029) and TS (p=0.017) in primary tissues were significantly associated with hematogenous metastasis. Patterns of the expression of the three enzymes varied, and were classified in six ways. A tendency was seen for primary colorectal cancer with DPD-high expression to have liver metastasis and for that with DPD-low expression, to have lung metastasis. CONCLUSION: High expression levels of OPRT and TS in colorectal cancer appear to be significantly involved in metastasis after curative surgery. The organs in which metastases arise may be controlled by the expression of DPD.

Orotate phosphoribosyl transferase (OPRT) is an essential nucleotide metabolic enzyme for cell proliferation and also a key enzyme for conversion of 5-FU to its active form in tumor tissue. The association between tumor OPRT activity and pathophysiological status, including lymph node metastasis [pN+], and the impact of OPRT for predicting pN+ were investigated in gastric cancer. The lymph node status of 73 resectable gastric cancer patients was analyzed preoperatively by computed tomography (CT), ultrasonography and magnetic resonance, and the OPRT activity of collected tumor tissue was measured. Then these data were compared with pathological observation of a surgical lymph node specimen. OPRT activity in the tumor tissue decreased as the depth of invasion increased. An OPRT test demonstrated superior sensitivity and comparable accuracy and sensitivity for predicting pN+, against current imaging diagnoses. Furthermore, the analysis of node negative patients by CT revealed that 80% of false negative patients were retrieved by this OPRT test. Thus, OPRT activity in tumor tissue was a powerful predictor of pN+ in resectable gastric cancer, and the preoperative OPRT test, when it becomes possible, would provide a basis for accurate evaluation of disease status, which is indispensable for the planning of personalized therapy.