In vivo inhibition by a site-specific catalytic RNA subunit of RNase P designed against the BCR-ABL oncogenic products: a novel approach for cancer treatment

One major obstacle to the effective treatment of cancer is to distinguish b etween tumor cells and normal cells. The chimeric molecules created by canc er-associated chromosomal abnormalities are ideal therapeutic targets becau se they are unique to the disease. We describe the use of a novel approach based on the catalytic RNA subunit of RNase P to destroy specifically the t umor-specific fusion genes created as a result of chromosome abnormalities. Using as a target model the abnormal BCR-ABL p190 and p210 products, we co nstructed M1-RNA with guide sequences that recognized the oncogenic messeng ers at the fusion point (M1-p190-GS and M1-p210-GS), To test the effectiven ess and the specificity of M1-p190-GS and M1-p210-GS, we studied in vitro a nd in vivo effects of these RNA enzymes against BCR-ABL(p190) and BCR-ABL(p 210) bearing in mind that both fusion genes share the ABL sequence but diff er in the sequence coming from the BCR gene. We showed that M1-p190-GS and M1-p210-GS can act as sequence-specific endonucleases and can exclusively c leave target RNA that forms a base pair with the guide sequence (GS), We al so demonstrated that when M1-p190-GS and M1-p210-GS were expressed in prope r mammalian cell models, they abolished the effect of BCR-ABL by specifical ly decreasing the amount of the target BCR-ABL mRNA and preventing the func tion of the BCR-ABL oncogenes. These data clearly demonstrate the usefulnes s of the catalytic activity of M1-GS RNA to cleave specifically the chimeri c molecules created by chromosomal abnormalities in human cancer and to rep resent a novel approach to cancer treatment. (C) 2000 by The American Society of Hematology.