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Basic and Translational Investigations |
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
2 Address correspondence to Dennis F. Deen, Brain Tumor Research Center, 505 Parnassus Ave., U-378, University of California San Francisco, San Francisco, CA 94143-0520, USA (ddeen{at}itsa.ucsf.edu).
Abstract
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 glioma-specific
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.
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