nature biotechnology
JUNE 1998 PRESS RELEASE
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Brain tumor molecular surgery
Investigators have succeeded in designing synthetic therapeutic RNA molecules that are 14,000 times more stable in the body than their natural counterparts. After a single injection, these small catalytic RNA molecules---molecular "scissors" termed ribozymes---were able to shrink human glioma brain tumors that had been transplanted into rats from 20 grams to almost 1 gram in only 20 days.
Human glioma cells express a messenger RNA molecule that encodes a mutant cell signaling protein---protein kinase C alpha (PKC)---that has been implicated in aberrant cell growth. Mouldy Sioud and Dag Sorensen set out to determine whether inhibition of this mutant PKC at the messenger RNA (mRNA) level by a ribozyme could halt tumor cell growth. They designed a ribozyme that would destroy the protein by attaching specifically to its aberrant mRNA sequence and snipping it out. But in order to make a ribozyme that could be used as a therapeutic, they had to find a way of making the molecule resistant to degradation by ribonuclease enzymes present in the blood.
By replacing a subset of nucleotides---the pyrmidine nucleotides---that make up the ribozyme with nuclease-resistant analogs, Sioud and Sorensen succeeded in creating a ribozyme that is much stabler than its natural ribonucleotide counterpart, yet retains its catalytic activity. This molecule was capable of reducing the level of the PKC mRNA in glioma cells, indicating that the abnormal activity of this enzyme is directly involved in abnormal cell proliferation. The authors then went further to show that an injection of the modified ribozyme into a rat containing human glioma tumors resulted in significant tumor shrinkage over a period of three weeks. Today, malignant gliomas are the third leading cause of death from cancer in individuals of 15 to 34 years of age, frequently failing to respond to irradiation, chemotherapy, or immunotherapy.
CONTACT:
Dr. Mouldy Sioud
Inst for Cancer Res, Dept. of Immunology
The Norwegian Radium Hospital
Montebello
N-0310 Oslo Norway
tel +47 22 93 45 63
fax +47 22 50 07 30
e-mail [email protected]
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