Cytotoxicity of N4-behenoyl-1-beta-D-arabinofuranosylcytosine through gradual conversion to 1-beta-D-arabinofuranosylcytosine in HeLa cells.
The metabolism of 1-beta-D-arabinofuranosylcytosine (ara-C) and N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC) was studied in Hela cells. After the cells were exposed to ara-C at a concentration of 20 micrograms/ml or BH-AC at 46.5 micrograms/ml for 1, 3, 6, 12 or 24 hr, the level of ara-C was determined using the radioimmunoassay method, and the level of BH-AC and 1-beta-D-arabinofuranosyluracil (ara-U), using high-performance liquid chromatography. In the ara-C-treated cells, the intracellular ara-C increased to 1.26 micrograms/g cells after exposure for 6 hr, and ara-C was rapidly changed to ara-U in the cells and in the medium. In the BH-AC-treated cells, the intracellular BH-AC increased after exposure for 24 hr and BH-AC was gradually converted to ara-C in the cells: the intracellular level of ara-C was only 15% of that of BH-AC after exposure for 24 hr. BH-AC level in the medium persisted for 24 hr, at the initial concentration. Our findings show that BH-AC is stable compared to ara-C and gradually converts to ara-C. This conversion is presumably a critical step in the antineoplastic effect of BH-AC.
Maehara
Y
Y
Cancer Center, Kyushu University Hospital, Fukuoka, Japan.
Kusumoto
T
T
Sakaguchi
Y
Y
Kusumoto
H
H
Anai
H
H
Sugimachi
K
K
D000970:Antineoplastic Agents / Q000378:metabolism*; D001086:Arabinofuranosyluracil / Q000378:metabolism; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans
D000970:Antineoplastic Agents; D003561:Cytarabine; D001086:Arabinofuranosyluracil; C015019:enocitabine