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Next Article 
Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 731-737
PLENARY PAPER
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
C. Cobaleda and
I. Sánchez-García
From the Department of Cell Growth and Differentiation, Institute of
Microbiology and Biochemistry, CSIC/University of Salamanca, Salamanca,
Spain.
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-ABLp190 and
BCR-ABLp210, 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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