Significance of Orotate Phosphoribosyltransferase Activity in Renal Cell Carcinoma

Abstract

The anticancer agent 5-fluorouracil (5-FU) is clinically used against various cancers, including renal cell carcinoma (RCC). It is a prodrug and orotate phosphoribosyltransferase (OPRT) is the principal enzyme that directly converts 5-FU to the active anticancer metabolite 5-fluoro-2'-deoxyuridine 5'-monophosphate. In addition, OPRT is the key enzyme in the de novo DNA and RNA synthetic process. Little is known about the significance of OPRT in various cancers, including RCC. We investigated the activity of OPRT in 83 RCCs and evaluated the association between the level of OPRT activity and the stage/grade of RCC. The relationship between OPRT activity in RCC cells and their sensitivity to 5-FU was also examined. OPRT activity in nonfixed, fresh frozen RCC and normal kidney was determined enzymatically by the 5-FU phosphorylation assay. The sensitivity of RCC cells to 5-FU was assessed by the microculture tetrazolium dye assay. The activity of OPRT was approximately 8.5-fold higher in RCC than in normal kidney. OPRT activity in stage III/IV RCC was 3-fold higher than in stage I/II RCC. The level of OPRT activity in grade 3 RCC was 3-fold higher than that in grade 1/2 cancer. Patients with RCC with low OPRT activity had longer postoperative disease specific survival than those with high activity at 5-year followup. OPRT activity in RCC cells positively correlated with their sensitivity to 5-FU. To our knowledge this is the first study to demonstrate that OPRT activity in RCC was higher than that in normal kidney and OPRT activity positively correlated with RCC stage/grade. In addition, higher OPRT activity in RCC predicted worse prognosis and higher sensitivity to 5-FU. These results suggest that the level of OPRT activity may be used as a prognostic parameter and predictive indicator for 5-FU efficacy in RCC and OPRT may be a molecular therapeutic target in RCC.