RB tumor suppressor gene expression responds to DNA synthesis inhibitors

Expression of the RB tumor suppressor gene, whose function is putatively in controlling cell growth, may be regulated by S-phase specific inhibitors of DNA synthesis that are commonly used in cell synchronization and cancer chemotherapy. Relatively low concentrations of the agents, cytosine arabinoside, bromodeoxyuridine, 5-fluorouracil, hydroxyurea, methotrexate and retinoic acid, were tested. At low concentrations still permitting submaximal cell growth, these drugs all changed RB gene expression, causing either up or down regulation of RB expression to varying degrees. Despite their potential similarity as a class, the nucleotide analogues elicited differential effects. The drug-induced up or down regulation of RB expression did not correlate with changes in c-myc expression indicating that the changes are not a manifestation of general metabolic changes potentially associated with altered proliferation. Amongst the agents considered, retinoic acid was the only one that caused a significant parallel reduction in RB and c-myc expression in the HL-60 human promyelocytic leukemia cells tested. The results thus show that even low concentrations of DNA synthesis inhibitors can have unpredictable affects on expression of growth regulatory genes.