Dual mechanisms of inhibition of DNA synthesis by triciribine.
The inhibition of DNA synthesis in triciribine (TCN)-treated L1210 cells was shown to involve two mechanisms, with different concentration dependence. (a) Initiation of new replicons and possibly of Okazaki fragments was inhibited when the cells were treated with 0.1 microM TCN. The inhibition of replicon initiation was shown by the rate of alkaline elution of [3H]DNA from 15-min-[3H]thymidine-labeled cells being slower if the cells had been pretreated with TCN, indicating that the average size of actively replicating DNA strands was increased. (b) At 1 microM TCN elongation of previously initiated DNA chains was also inhibited. This conclusion was suggested by the decrease in the rate of alkaline elution of [3H]DNA, during postlabeling incubation, being less if TCN was included in the medium. The mechanism of inhibition of DNA synthesis by TCN was shown not to involve DNA strand breakage or cross-linking, inhibition of polyamine biosynthesis, inhibition of purine de novo biosynthesis, inhibition of DNA polymerase alpha or DNA primase, or inhibition of ligation of Okazaki fragments. The effects of TCN on the incorporation of [3H]thymidine into Okazaki fragments and higher molecular weight DNA suggested the possibilities of inhibition of Okazaki fragment initiation and/or DNA polymerase delta.
Wotring
L L
LL
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Townsend
L B
LB
Jones
L M
LM
Borysko
K Z
KZ
Gildersleeve
D L
DL
Parker
W B
WB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004256:DNA Polymerase I / Q000378:metabolism; D019915:DNA Primase; D004261:DNA Replication / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000302:isolation & purification; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D011700:Putrescine / Q000378:metabolism; D012316:RNA Nucleotidyltransferases / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D012263:Ribonucleosides; C023764:triciribine; D013096:Spermine; D019915:DNA Primase; D012316:RNA Nucleotidyltransferases; D004256:DNA Polymerase I; D013095:Spermidine; D011700:Putrescine; D013936:Thymidine