Cytotoxicity and the inhibition of ribosomal RNA processing in human colon carcinoma cells.

The effects of six nucleoside and base analogs, 5-fluorouracil, 5-azacytidine, sangivamycin, toyocamycin, 8-azaguanine, and tubercidin, on ribosomal RNA processing and cell viability were examined in the colon carcinoma cell line HT-29. Exposure of HT-29 cells to various concentrations of each of these compounds for 24 hr produced two distinct types of results. Toyocamycin, 5-fluorouracil, and tubercidin caused an exponential type of cell lethality resulting in 3-4 log reduction of cell viability, while sangivamycin, 8-azaguanine, and 5-azacytidine produced a gradual and self-limiting type of cell lethality resulting in no greater than a 1 log reduction of cell viability. Likewise, the effects of these drugs on rRNA processing resulted in their classification into two groups: toyocamycin, 5-fluorouracil, and tubercidin caused an abnormal accumulation of the 45 S precursor to rRNA, while sangivamycin, 8-azaguanine, and 5-azacytidine did not cause an accumulation of 45 S RNA. Sangivamycin, 8-azaguanine, and 5-azacytidine all produced an inhibitory effect on protein synthesis, while tubercidin inhibited protein synthesis at a concentration similar to that which caused the accumulation of 45 S RNA, and toyocamycin and 5-fluorouracil had no effect on protein synthesis at concentrations at which 45 S RNA accumulated. These results show that cells are much less capable of resuming normal proliferative activity after exposure to nucleoside or base analogs which cause the accumulation of 45 S rRNA precursor, than to those which act by other mechanisms.