The effects of
3-cyclohexyl-6,7-dihydro-1H-cyclopentapyrimidine-2,4(3H,5H)-dione (
lenacil) on macromolecular synthesis, thymidilate
synthetase activity, viability and cell cycle progression were studied using Friend
leukemia (FL). P388 and
Ehrlich ascites tumor cells in
suspension, and its cytogenetic effects were studied in a Salmonella/mammalian microsome assay using both frameshift and base-substitution tester strains. At a concentration of 0.5 mmol/l
lenacil inhibited 45 to 70%
thymidine incorporation into
DNA fraction, while incorporations of
uridine into
RNA and
leucine into
protein were less affected. Thymidilate
synthetase activity in P388 cells as assayed by the release of tritiated water from 5-3H-deoxyuridine was inhibited by the compound to about 20%.
Lenacil neither showed an in vivo inhibitory action on
thymidine incorporation into
acid-insoluble material in P388 cells, nor on thymidilate
synthetase activity after a 24 or 48 h treatment. The compound did not change the melting temperature of isolated
DNA. Studies of
lenacil's effect on cell cycle kinetics of FL cells demonstrated that 48 h treatment increased the percentage of S-phase cells.
Lenacil exerted a weak cytotoxic effect on FL cells. At concentrations above 0.1 mmol/l it inhibited cell growth the effect being nonlethal. Cytogenetic studies of
lenacil revealed no indication of its mutagenicity against Salmonella typhimurium TA97, TA98, TA100 and TA102.