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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.

Abstract
One major obstacle to the effective treatment of cancer is to distinguish between tumor cells and normal cells. The chimeric molecules created by cancer-associated chromosomal abnormalities are ideal therapeutic targets because 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 tumor-specific fusion genes created as a result of chromosome abnormalities. Using as a target model the abnormal BCR-ABL p190 and p210 products, we constructed M1-RNA with guide sequences that recognized the oncogenic messengers at the fusion point (M1-p190-GS and M1-p210-GS). To test the effectiveness and the specificity of M1-p190-GS and M1-p210-GS, we studied in vitro and in vivo effects of these RNA enzymes against BCR-ABL(p190) and BCR-ABL(p210), bearing in mind that both fusion genes share the ABL sequence but differ 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 cleave target RNA that forms a base pair with the guide sequence (GS). We also demonstrated that when M1-p190-GS and M1-p210-GS were expressed in proper mammalian cell models, they abolished the effect of BCR-ABL by specifically decreasing the amount of the target BCR-ABL mRNA and preventing the function of the BCR-ABL oncogenes. These data clearly demonstrate the usefulness of the catalytic activity of M1-GS RNA to cleave specifically the chimeric molecules created by chromosomal abnormalities in human cancer and to represent a novel approach to cancer treatment.
AuthorsC Cobaleda, I Sánchez-García
JournalBlood (Blood) Vol. 95 Issue 3 Pg. 731-7 (Feb 01 2000) ISSN: 0006-4971 [Print] United States
PMID10648380 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • RNA, Catalytic
  • RNA, Messenger
  • RNA, Neoplasm
  • Fusion Proteins, bcr-abl
  • Endoribonucleases
  • RPP14 protein, human
  • Ribonuclease P
Topics
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Base Sequence
  • Drug Design
  • Endoribonucleases (chemistry)
  • Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Genes, abl
  • Humans
  • Mice
  • Molecular Sequence Data
  • Neoplasms (drug therapy)
  • Oncogenes
  • RNA, Catalytic (chemistry, pharmacology, therapeutic use)
  • RNA, Messenger (biosynthesis)
  • RNA, Neoplasm (biosynthesis)
  • Ribonuclease P
  • Substrate Specificity
  • Transfection
  • Tumor Cells, Cultured

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