RNA cleavage and inhibition of protein synthesis by bleomycin.
Bleomycin is a clinically used antitumor antibiotic long thought to function therapeutically at the level of DNA cleavage. Recently, it has become clear that bleomycin can also cleave selected members of all major classes of RNA. Using the computer program COMPARE to search the database established by the Anticancer Drug Screening Program of the National Cancer Institute, a possible mechanism-based correlation was found between onconase, an antitumor ribonuclease currently being evaluated in phase III clinical trials, and the chemotherapeutic agent bleomycin. Following these observations, experimentation revealed that bleomycin caused tRNA cleavage and DNA-independent protein synthesis inhibition in rabbit reticulocyte lysate and when microinjected into Xenopus oocytes. The correlation of protein synthesis inhibition to the previously reported site-specific RNA cleavage caused by bleomycin supports the thesis that RNA cleavage may constitute an important element of the mechanism of action of bleomycin.
Abraham
Anil T
AT
Department of Chemistry, University of Virginia, Charlottesville, VA 22901, USA.
Lin
Jih-Jing
JJ
Newton
Dianne L
DL
Rybak
Susanna
S
Hecht
Sidney M
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002474:Cell-Free System; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D009865:Oocytes; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012313:RNA / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D012156:Reticulocytes; D012260:Ribonucleases / Q000378:metabolism / Q000494:pharmacology; D012984:Software; D014981:Xenopus
D000970:Antineoplastic Agents; D011500:Protein Synthesis Inhibitors; D001761:Bleomycin; D012313:RNA; D012260:Ribonucleases; C058703:ranpirnase