Combinations of 5-fluorouracil with UCN-01 or staurosporine.

The action of 5‐Fluorouracil (5‐FU) is mediated by inhibition of thymidylate synthase (TS), which is regulated by cell cycle proteins controlled by protein phosphorylation. We studied the effects of staurosporine and its analogue UCN‐01, inhibitors of protein kinase C (PKC) on 5‐FU cytotoxicity in Lovo colon cancer cells. Each drug contributes equally to the cell cycle effects of the 5‐FU combinations. In sequential drug administration, the cell cycle distribution was determined by the first drug. Simultaneous 5‐FU combinations induced additive effects in induction of apoptosis. When staurosporine was used as the second drug, induction of apoptosis was 2‐fold higher than the sum of both drugs alone. Based on induction of apoptosis 5‐FU addition prior to the PKC inhibitors seemed preferable.