Circumvention of drug resistance in cancer cells by a new fluoropyrimidine analogue

Abstract

The potentiation of antitumor drugs by their analogues is one of strategies for overcoming cellular resistance to chemotherapy. In attempts to improve the efficacy of 5-fluorouracil (5-FU) and overcome 5-FU resistance, we synthesized new 5- FU derivatives and evaluated the potentiation effect on 5-FU cytotoxicity. 5-Fluorouracil-1-yl-3-butanone (5-FUBO), a newly synthesized 5-FU derivative, significantly potentiated the cytotoxic effect of 5-FU, and the potentiation of 5-FU by 5-FUBO in 5-FU resistant cells was higher than in their drugsensitive parental cells. Surprisingly, it potentiated the cytotoxicities of vincristine and vinblastine. The potentiation of these drugs by 5-FUBO in mutidrugresistant (MDR) cells was more than in their drugsensitive parental cells. It was also shown that 5-FUBO increased the intracellular accumulation of [3H]vincristine in P388/M cells, and this is related with increased cytotoxicity of vincristine. Northern blot analysis showed that the potentiation effect of MDR-related antitumor drugs by 5-FUBO was caused by inhibition of MDRl gene expression. Also, 5-FUBO cytotoxicity in K562 cells was increased significantly upon transformation with c-Ha-ras.