5-FLUOROURACIL INTERFERES WITH PACLITAXEL CYTOTOXICITY AGAINST HUMAN SOLID TUMOR-CELLS

Paclitaxel, a naturally occurring antimitotic agent, has shown efficac y in the treatment of certain solid tumors, particularly metastatic br east carcinoma and drug-refractory ovarian cancers, Recent studies hav e demonstrated that paclitaxel, in addition to its effects on microtub ules and cell cycle arrest, possesses significant cell-killing activit y in solid tumor cells by the induction of apoptosis, However, the mec hanism by which paclitaxel leads to cell death and its relationship wi th paclitaxel-induced mitotic arrest is presently unclear, In this stu dy, we attempted to determine whether pre-arresting tumor cells at oth er phases of the cell cycle could affect paclitaxel-induced apoptosis, We found that 5-fluorouracil (5-FU), another antineoplastic agent tha t usually arrests tumor cells at the G(1)-S phase of the cell cycle, c ould significantly repress the cell-killing activity of paclitaxel in solid tumor cells, even when it was added simultaneously with paclitax el, Further studies indicated that 5-FU actually inhibits the cytotoxi c effects of paclitaxel on both mitotic arrest and apoptotic cell deat h, suggesting that 5-FU might interfere with paclitaxel cytotoxicity a t an early stage, probably by preventing tumor cells from entering G(2 )-M phase, Because recent clinical trials have used a combination of p aclitaxel and 5-FU in the treatment of metastatic breast cancers, our results also suggest that the combination of these two drugs might not be as valuable in clinical chemotherapy.