Antagonistic interplay between antimitotic and G1-S arresting agents observed in experimental combination therapy.
Paclitaxel is a naturally occurring antimitotic agent that has been shown to stabilize microtubules, induce mitotic arrest, and ultimately induce apoptotic cell death. The favorable clinical activity of paclitaxel has prompted considerable interest in combining paclitaxel with numerous other antineoplastic agents. Our previous studies have suggested 5-fluorouracil (5-FU), an antineoplastic agent that usually arrests tumor cells at the G1-S phase of the cell cycle, in combination with paclitaxel significantly represses paclitaxel-induced mitotic arrest and apoptosis. In the present study, we have extended this investigation to include several other antimitotic agents (vinblastine, colchicine, and nocodazole) in various combination schedules with the G1-S arresting agents 5-FU and hydroxyurea (HU). We found 5-FU, as well as HU, could significantly interfere with the overall cytotoxicity as compared with treatment with antimitotic agents alone. It appeared that 5-FU or HU severely limited the antimitotic agents' cytotoxic effects on both mitotic arrest and apoptosis. No combination of a G1-S arresting agent with an antimitotic agent in any schedule produced an antitumor effect greater than that of the antimitotic agent alone. In addition, biochemical examination revealed that 5-FU and HU blocked the antimitotic agent-induced increase of p21WAF1/CIP1 protein levels, as well as prevented the hyperphosphorylation of the bcl-2 and c-raf-1 proteins. These findings suggest that careful considerations may be necessary when combining antineoplastic agents that exert their cytotoxic action at different phases of the cell cycle.
Johnson
K R
KR
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston 29425, USA.
Young
K K
KK
Fan
W
W
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D007624:KB Cells; D017239:Paclitaxel / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D019908:Proto-Oncogene Proteins c-raf; D017239:Paclitaxel; D005472:Fluorouracil; D006918:Hydroxyurea