SCHEDULE-DEPENDENT ENHANCEMENT OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE INCORPORATION INTO HL-60 DNA BY DEOXYGUANOSINE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (4) , 1530-1535
Abstract
The ability was studied of the purine deoxynucleoside deoxy-guanosine (dGuo) to enhance 1.beta.-D-arabinofuranosylcytosine (ara-C) [an antitumor agent] incorporation into DNA of HL-60 cultured human leukemia cells. The effects of dGuo on ara-C incorporation into DNA were compared to those of thymidine (dThd), a pyrimidine deoxynucleoside known to augment ara-C effects both in vitro and in vivo. Both deoxynucleosides doubled the cells in the S phase of the cell cycle within the exposure periods (up to 48 h) and concentrations (10-1000 .mu.M) tested. Both deoxynucleosides enhanced ara-C incorporation into DNA equally. dThd and dGuo differed in the schedule required to achieve this effect. Simultaneous exposure to cells to ara-C and dThd increased ara-C incorporation into DNA .apprx. 3.5-fold. Preincubation of cells with dThd for 16 h prior to the addition of ara-C further enhanced ara-C incorporation into DNA (to .apprx. 5-fold) in direct proportion to the dThd-induced increase in cells in S phase. Preincubation was essential for dGuo, since 16-h preincubation of cells with concentrations as low as 30 .mu.M caused augmentation of ara-C incorporation into DNA; but simultaneous exposure of cells to dGuo and ara-C caused no augmentation of ara-C incorporation into DNA. The augmentation of ara-C incorporation into DNA caused by preincubation of the cells with dGuo results from a number of factors, including the cytokinetic effect of increasing the percentage of cells in S phase and the reduction of intracellular dCTP pools. Maximal dGuo enhancement of ara-C incorporation into DNA (.apprx. 5-fold) required > 100 .mu.M dGuo, 16-h preincubation with dGuo, and final incubation of cells with ara-C after removal of dGuo. This further augmentation of ara-C incorporation into DNA caused by the removal of dGuo prior to adding ara-C was explained by the observed inhibition of ara-C phosphorylation by dGuo concentrations > 100 .mu.M.