Comparison of the effects of several inhibitors of the synthesis of nucleic acids upon the viability and progression through the cell cycle of cultured H. Ep. no. 2 cells.

Abstract

Summary The effects of arabinosylcytosine, hydroxyurea (HU), guanazole (Gz), 5-fluorodeoxyuridine, methotrexate, 6-mercaptopurine, 6-methylthiopurine ribonucleoside, 6-thioguanine, and 5-fluorouracil (5-FUra) upon the viability and progression through the cell cycle of cultured H. Ep. No. 2 cells have been determined. Similarities and differences were found. When the logarithm of the surviving fraction after an exposure period equal to T C was plotted versus concentration of the agent, only 5-FUra yielded an exponential curve. With all of the other agents, the curves flattened for higher concentrations, which shows that increasing the concentrations of these agents beyond certain levels does not increase cell kill during a 26-hr exposure period. Thus, only 5-FUra could be expected to cause “total cell kill” under these conditions. None of the agents prevented the cells that were initially in G 2 from progressing to mitosis. All of the agents retarded or prevented progression to mitosis of cells initially in S but, by the end of a period of exposure equal to T C , essentially all of the cells initially in S and exposed to 6-mercaptopurine, 6-methylthiopurine ribonucleoside, and the lower concentrations of 5-FUra reached mitosis. All of the agents prevented cells initially in G 1 from progressing to mitosis during an exposure period equal to T C . Arabinosylcytosine, HU, Gz, methotrexate, 5-fluorodeoxyuridine, and 5-FUra caused partial synchronization of the cultures at or near the G 1 -S transition stage. (This blocking effect might protect some of the cells from the agents by preventing them from progressing to a more sensitive stage of the cycle.) There was no evidence that 6-mercaptopurine, 6-methylthiopurine ribonucleoside, and 6-thioguanine caused synchronization. It is probable that the concentrations of HU and Gz decreased during the 26-hr incubation with H. Ep. No. 2 cells. It appears that arabinosylcytosine, HU, and Gz are more effectively removed from the cells by washing than are the other agents.