Deoxypyrimidine-induced inhibition of the cytokinetic effects of 1-beta-D-arabinofuranosyluracil.
Ara-U-induced S-phase accumulation and the interaction between high concentrations of ara-U (HiCAU) and ara-C were investigated in L1210 leukemia cells in vitro. Treatment of exponentially growing L1210 murine leukemia cells with ara-U (200-1000 microM) for 48 h caused a dose-dependent accumulation of cells in the S-phase. The extent of this ara-U-induced S-phase accumulation correlated with ara-U incorporation into DNA and with increases of up to 172% and 464% in the specific activities of deoxycytidine kinase and thymidine kinase, respectively, over control values. Metabolism of 1 microM ara-C following the exposure of cells to ara-U (1 mM) resulted in 4.5 pmol araC DNA/mg protein vs 2.1 pmol/mg protein in control cells. Although 48-h exposure of cells to 200 and 400 microM ara-U is not cytotoxic, it enhances the cytotoxicity of ara-C (10-100 microM) 4- to 10-fold. Ara-U-induced S-phase accumulation is inhibited by deoxypyrimidine nucleosides but not by pyrimidine or deoxypurine nucleosides. Some of the ara-U and ara-C concentrations used in this study are achievable in clinical practice, and ara-U/ara-C interactions may explain in part the unique therapeutic utility of high-dose ara-C.
Chandrasekaran
B
B
Comprehensive Cancer Center, Wake Forest University Winston-Salem, NC 27103.
Kute
T E
TE
Capizzi
R L
RL
D000818:Animals; D001086:Arabinofuranosyluracil / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009705:Nucleosides / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D013937:Thymidine Kinase / Q000187:drug effects / Q000378:metabolism
D004273:DNA, Neoplasm; D009705:Nucleosides; D011743:Pyrimidines; D003561:Cytarabine; D001086:Arabinofuranosyluracil; D013937:Thymidine Kinase; D003842:Deoxycytidine Kinase