Long intracellular retention of 4′-thio-arabinofuranosylcytosine 5′-triphosphate as a critical factor for the anti-solid tumor activity of 4′-thio-arabinofuranosylcytosine

Autor: Hitoshi Someya, William B. Parker, William R. Waud
Rok vydání: 2005
Předmět:
Zdroj: Cancer Chemotherapy and Pharmacology. 57:772-780
ISSN: 1432-0843
0344-5704
DOI: 10.1007/s00280-005-0126-0
Popis: 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.
Databáze: OpenAIRE
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