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.
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Authors | C Cobaleda, I Sánchez-García |
Journal | Blood
(Blood)
Vol. 95
Issue 3
Pg. 731-7
(Feb 01 2000)
ISSN: 0006-4971 [Print] United States |
PMID | 10648380
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- RNA, Catalytic
- RNA, Messenger
- RNA, Neoplasm
- Fusion Proteins, bcr-abl
- Endoribonucleases
- RPP14 protein, human
- Ribonuclease P
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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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