Synergistic inhibition of human gastric carcinoma cell growth by 1-beta-D-arabinofuranosylcytosine and hydroxyurea or 2'-deoxyguanosine in vitro.
The cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C) in combination with hydroxyurea (HU) or 2'-deoxyguanosine (GdR) on human gastric carcinoma MK-1 cells and colon carcinoma HT-15 cells was studied. Synergistic interaction between ara-C and HU on MK-1 cells and HT-15 cells, or ara-C and GdR on MK-1 cells was shown using the combination index method. HU increased the accumulation of ara-C triphosphate (ara-CTP) in the acid-soluble pool and diminished the cellular deoxyCTP (dCTP) pool. HU had no effect on the incorporation of ara-C into DNA and RNA. These results indicate that HU-induced elevation in ara-CTP and decrease in dCTP are the basis for synergy among ara-C and HU in MK-1 cells. GdR diminished cellular dCTP slightly, but it decreased the accumulation of ara-CTP in the acid-soluble pool and did not increase the incorporation of ara-C into DNA. On the other hand, ara-C increased cellular deoxyGTP (dGTP) level in the presence of GdR. These results indicate that synergy between ara-C and GdR is mediated through increased cellular dGTP which might inhibit DNA synthesis directly.
Matsumoto
M
M
Department of Biochemistry, Tokai University School of Medicine, Kanagawa, Japan.
Kawahara
T
T
Tsuda
M
M
Ohkubo
T
T
Kamiguchi
H
H
Yamamura
M
M
D002277:Carcinoma / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D003561:Cytarabine / Q000008:administration & dosage*; D003849:Deoxyguanosine / Q000008:administration & dosage*; D003854:Deoxyribonucleotides / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage*; D066298:In Vitro Techniques; D013274:Stomach Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D003854:Deoxyribonucleotides; D003561:Cytarabine; D003849:Deoxyguanosine; D006918:Hydroxyurea