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Antitumor effects of specific telomerase
inhibitor GRN163 in human glioblastoma xenografts
Tomoko Ozawa, Sergei M. Gryaznov, Lily J. Hu, Krisztina Pongracz, Raquel
A. Santos, Andrew W. Bollen, Kathleen R. Lamborn, Dennis F. Deen
Brain Tumor Research Center of
the Department of Neurological Surgery (T.O., L.J.H., R.A.S., K.R.L., D.F.D.)
and Department of Pathology (A.W.B.), University of California San Francisco,
San Francisco, CA 94143-0520; and Geron Corporation, Menlo Park, CA 94025
(S.M.G., K.P.); USA
Telomerase is a ribonucleoprotein complex that elongates telomeric DNA and
appears to play an important role in cellular immortalization of cancers.
Because telomerase is expressed in the vast majority of malignant gliomas but
not in normal brain tissues, it is a logical target for gliomaspecific
therapy.
The telomerase inhibitor GRN163, a 13-mer oligonucleotide N3' P5' thio-phosphoramidate
(Geron Corporation, Menlo Park, Calif.), is complementary to the template region
of the human telomerase RNA subunit hTR.
When athymic mice bearing U-251 MG human brain tumor xenografts in their flanks
were treated intratumorally with GRN163, a significant growth delay in tumor
size was observed (P < 0.01 in all groups) as compared to the tumor
size in mice receiving a mismatched oligonucleotide or the carrier alone.
We also investigated biodistribution of the drug in vivo in an intracerebral rat
brain-tumor model.
Fluorescein-labeled GRN163 was loaded into an osmotic minipump and infused
directly into U-251 MG brain tumors over 7 days.
Examination of the brains revealed that GRN163 was present in tumor cells at all
time points studied.
When GRN163 was infused into intracerebral U-251 MG tumors shortly after their
implantation, it prevented their establishment and growth.
Lastly, when rats with larger intracerebral tumors were treated with the
inhibitor, GRN163 increased animal survival times.
Our results demonstrate that the antitelomerase agent GRN163 inhibits growth of
glioblastoma in vivo, exhibits favorable intracerebral tumor uptake properties,
and prevents the growth of intracerebral tumors.
These findings support further development of this compound as a potential
anticancer agent.
© 2004 Duke University Press
Source: http://zerlina.ingentaselect.com/vl=15704931/cl=99/nw=1/rpsv/cgi-bin/linker?ini=dup_no&reqidx=/cw/dup/15228517/v6n3/s5/p218
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