Combined cytotoxic effect of low-dose 5-fluorouracil and hydroxyurea on 9L cells in vitro.
Continuous exposure of exponentially growing 9L rat brain tumor cells for 24 hr to a nontoxic dose (0.77 microM) of 5-fluorouracil (5-FUra) produced a progressive increase in S-phase cells from 35% (asynchronous culture) to 70% as shown by DNA histograms based on data obtained by flow cytometry. When 9L cells were treated with the S-phase-specific agent hydroxyurea (1.3 mM) immediately after treatment with 5-FUra, a synergistic cell kill resulted. A centrifugal elutriation study confirmed that enhanced cell kill was caused in part by the S-phase synchrony produced by 5-FUra and to the S-phase specificity of hydroxyurea. A higher dose (7.7 microM) of 5-FUra caused a partial G1-S block; subsequent treatment with hydroxyurea also enhanced cell kill, but the enhancement was not related to S-phase synchrony. A centrifugal elutriation study suggested that, after 24-hr treatment with 5-FUra, hydroxyurea might kill both cells in S phase, which has the greater number of clonogenic cells, and kill cells that are in other phases of the cell cycle, including cells blocked at the G1-S border that are vulnerable to the phenomenon of "thymidineless death"; concomitant administration of thymidine along with 5-FUra eliminated enhanced cell kill.
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000627:therapeutic use / Q000633:toxicity*; D006918:Hydroxyurea / Q000627:therapeutic use / Q000633:toxicity*; D007700:Kinetics; D051381:Rats; D013936:Thymidine / Q000494:pharmacology
D005472:Fluorouracil; D013936:Thymidine; D006918:Hydroxyurea