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.
Cohen
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Glazer
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D001374:Azacitidine / Q000494:pharmacology; D001375:Azaguanine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D014176:Protein Biosynthesis; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D012335:RNA, Ribosomal / Q000378:metabolism*; D014127:Toyocamycin / Q000494:pharmacology; D014372:Tubercidin / Q000494:pharmacology
D011741:Pyrimidine Nucleosides; D012335:RNA, Ribosomal; C005699:sangivamycin; D014127:Toyocamycin; D014372:Tubercidin; D001374:Azacitidine; D001375:Azaguanine; D005472:Fluorouracil