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.
Sigmond
J
J
Department of Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Comijn
E M
EM
Kamphuis
J A E
JA
Peters
G J
GJ
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002469:Cell Separation; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D020128:Inhibitory Concentration 50; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D019311:Staurosporine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D019311:Staurosporine; D005472:Fluorouracil