5-Fluorouracil interferes with paclitaxel cytotoxicity against human solid tumor cells.
Paclitaxel, a naturally occurring antimitotic agent, has shown efficacy in the treatment of certain solid tumors, particularly metastatic breast carcinoma and drug-refractory ovarian cancers. Recent studies have demonstrated that paclitaxel, in addition to its effects on microtubules and cell cycle arrest, possesses significant cell-killing activity in solid tumor cells by the induction of apoptosis. However, the mechanism by which paclitaxel leads to cell death and its relationship with paclitaxel-induced mitotic arrest is presently unclear. In this study, we attempted to determine whether pre-arresting tumor cells at other phases of the cell cycle could affect paclitaxel-induced apoptosis. We found that 5-fluorouracil (5-FU), another antineoplastic agent that usually arrests tumor cells at the G1-S phase of the cell cycle, could significantly repress the cell-killing activity of paclitaxel in solid tumor cells, even when it was added simultaneously with paclitaxel. Further studies indicated that 5-FU actually inhibits the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death, suggesting that 5-FU might interfere with paclitaxel cytotoxicity at an early stage, probably by preventing tumor cells from entering G2-M phase. Because recent clinical trials have used a combination of paclitaxel 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.
Johnson
K R
KR
Department of Pathology, Experimental Oncology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Wang
L
L
Miller
M C
MC
Willingham
M C
MC
Fan
W
W
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007624:KB Cells / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D017239:Paclitaxel; D005472:Fluorouracil