Long intracellular retention of 4'-thio-arabinofuranosylcytosine 5'-triphosphate as a critical factor for the anti-solid tumor activity of 4'-thio-arabinofuranosylcytosine.
4'-Thio-arabinofuranosylcytosine (T-araC) is a new cytosine analog, which exhibits excellent antitumor activity against various solid tumor xenografts in mice. T-araC is a structural analog of arabinofuranosylcytosine (araC), which is known to be marginally active against solid tumors. We have continued to study the biochemical pharmacology of T-araC in solid tumor cells to further characterize the mechanism of action of this new agent and to elucidate why these compounds show a profound difference in antitumor activity against solid tumors. AraC was a slightly more potent inhibitor of cell growth than T-araC when cells were continuously exposed to the drugs. However, T-araC was markedly more cytotoxic than araC when high concentrations of the compounds were given for short periods of time. Despite the fact that T-araC is a much poorer substrate, as compared to araC, for deoxycytidine kinase (the rate-limiting step in the formation of the triphosphates), similar intracellular concentrations of T-araC-5'-triphosphate (T-araCTP) and araCTP were formed in cells at these high, pharmacologically relevant concentrations due to similar Vmax's. The major difference in the metabolism of araC and T-araC was that the half-life of T-araCTP was tenfold longer than that of araCTP and much higher levels of T-araCTP were sustained in cells for long durations after exposure to T-araC. Inhibition of cytidine deaminase, deoxycytidylate deaminase, or DNA replication did not affect the half-life of either araCTP or T-araCTP. In addition, the rates of disappearance of the mono- and tri-phosphates of araC and T-araC in crude cell extracts were similar. These results indicated that these enzymes were not rate-limiting in the degradation of the respective triphosphates. However, the rate of phosphorylation of T-araC-5'-monophosphate (T-araCMP) in crude cell extracts was about tenfold greater than that of araCMP. The results of this work suggested that the longer intracellular retention of T-araCTP was responsible for the superior activity of T-araC against solid tumors in vivo, and that the greater activity of T-araCMP as a substrate of UMP/CMP kinase was responsible for the long intracellular half-life of T-araCTP.
Someya
Hitoshi
H
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Waud
William R
WR
Parker
William B
WB
D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001087:Arabinonucleosides / Q000493:pharmacokinetics* / Q000494:pharmacology; D001088:Arabinonucleotides / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000493:pharmacokinetics* / Q000494:pharmacology; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006207:Half-Life; D006801:Humans
C511492:4'-thioarabinofuranosylcytosine triphosphate; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D001088:Arabinonucleotides; D003561:Cytarabine; D003570:Cytidine Triphosphate; D004247:DNA; C411255:4'-thio-arabinofuranosylcytosine