Potentiation of ara-C induced cytotoxicity by hydroxyurea in LoVo colon carcinoma cells.
The present study was undertaken to determine whether cytotoxicity by 1-beta-D-arabinofuranosylcytosine (ara-C) in LoVo colon carcinoma cells, which are resistant to high concentrations of ara-C, would be enhanced by concurrent exposure to hydroxyurea (HU). Since mechanisms underlying the effects of HU on ara-C induced cytotoxicity are unclear, we also evaluated the effect of HU on the incorporation of ara-C into DNA, as well as potential consequences of misincorporation. Our results demonstrate that HU synergistically enhances cytotoxicity by ara-C in these cells. This effect was not present when HU was combined with aphidicolin, an agent that resembles ara-C in competing with dCTP for binding to polymerase alpha but that is not incorporated into DNA. Further, cells exposed to HU and ara-C incorporated up to 5-fold as much ara-C into DNA as cells solely treated with ara-C. While the extent of inhibition of DNA synthesis was comparable with cells exposed to HU and aphidicolin as those treated with HU and ara-C, recovery of DNA synthesis was delayed more significantly by the latter combination. These findings suggest that HU synergistically potentiates ara-C induced cytotoxicity by enhancing incorporation of ara-C in LoVo cell DNA.
D016590:Aphidicolin; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D004224:Diterpenes / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D006918:Hydroxyurea / Q000494:pharmacology*
D004224:Diterpenes; D003561:Cytarabine; D016590:Aphidicolin; D004247:DNA; D006918:Hydroxyurea