Fluoropyrimidine-mediated changes in small nuclear RNA

Abstract

Studies were completed to examine the effects of the antineoplastic agent 5-Fluorouridine (FUrd) on the metabolism of the small molecular weight nuclear RNA (snRNA). Cultured Sarcoma-180 murine tumor cells were exposed to FUrd concurrent with [3H]cytidine for 6 h, the drug was removed, and the RNA was isolated at 0, 24, or 48 h following the drug treatment. The results of these studies demonstrated that FUrd produced three dose-dependent changes in snRNA metabolism. The electrophoretic migration of the U4 and U6 snRNA was altered in nondenaturing 10% polyacrylamide slab gels. These results were not observed in denaturing gels or when RNA was extracted at temperatures exceeding 25 degrees C, suggesting that the incorporation of 5-fluorouracil induced secondary structural changes in these RNA. A dose- and time-dependent selective reduction in the turnover of the U1 snRNA synthesized in the presence of FUrd was observed as well, with levels over 100% higher than control cells at 48 h after exposure to 10 microM FUrd. These changes in snRNA metabolism may contribute to the reported alterations in large molecular weight RNA metabolism that also result in fluoropyrimidine-treated cells, or to cytotoxicity.