Enhanced orotate phosphoribosyltransferase activity in renal cell carcinoma and its prognostic significance

Abstract

15590 Background: 5-Fluorouracil ( 5-FU ) is an anticancer agent clinically used against various cancers including renal cell carcinoma ( RCC ). 5-FU is a prodrug and orotate phosphoribosyltransferase ( OPRT ) is the principal enzyme which directly converts 5-FU to an active anticancer metabolite, 5-fluoro-2’-deoxyuridine 5’-monophosphate. Furthermore, OPRT is the key enzyme in the de novo DNA and RNA synthetic process, which converts orotic acid to orotidine 5’-phosphate. Little is known about the significance of OPRT in a variety of cancers including RCC. We investigated OPRT activity in 83 RCC and evaluated the association between 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. Methods: OPRT activity in non-fixed fresh frozen RCC and normal kidney were determined enzymatically by the 5-FU phosphorylation assay. The sensitivity of RCC cells to 5-FU was assessed by the microculture tetrazolium dye assay. Results: OPRT activity was approximately 8.5-fold higher in RCC compared to normal kidney. OPRT activity in T3/4 RCC was 3-fold higher than that in T1/2 RCC. OPRT activity in M1 RCC was 2.5-fold higher than that in M0 RCC. In addition, OPRT activity in Stage III/IV RCC was 3-fold higher than that 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 a longer postoperative disease-specific survival than those with high activity in the 5-year follow-up. OPRT activity in RCC cells positively correlated with their sensitivity to 5-FU. Conclusions: The present study has demonstrated that OPRT activity in RCC was higher than that in normal kidney, and that OPRT activity positively correlated with the stage/grade of RCC. Moreover, higher OPRT activity in RCC predicted worse prognosis and higher sensitivity to 5-FU. These results suggest that OPRT activity may be used as both a prognostic parameter and a predictive indicator for 5-FU efficacy in RCC. No significant financial relationships to disclose.