Results:: GRN163L efficiently inhibited telomerase activity in all the groups, showing a significant reduction in PlatingEfficiency with longer exposure times. Cells exposed to GRN163L for longer periods of time had significantly lowerproliferation rates. TRF assay showed a progressive telomere length reduction with longer exposure to GRN163L, explainingthe progressive decrease in proliferation observed. Our findings suggest that treatment with GRN163L for 9 or 20 dayssignificantly decreases the proliferation rate. Longer treatment (42 days) with GRN163L and clinically relevant doses of IR (2and 4 Gy) resulted in additive interactions at 2 Gy reducing survival from 36% to 4% (p�0.01), and synergistic cell killing at4 Gy reducing survival from 10% to 7% (p�0.01).

Conclusions: These results support that telomerase inhibition is a promising cancer treatment in combination with radiationtherapy that may improve the therapeutic index through a synergistic effect enhancing the radiation sensitivity in longerexposure times and a decrease in proliferation in shorter exposure times.

Author Disclosure: J. Gomez-Millan, None; E.M. Goldblatt, None; S.M. Gryaznov, Geron Corporation, A. Employment; M.S.Mendonca, None; B. Herbert, None.

2630 A Preclinical Human Tumor Model for Non-Invasive Imaging of Hypoxia-Induced Gene Expression;Comparison of Endogenous and Exogenous Markers of Tumor Hypoxia

F. He, Y. Huang, B. Wen, X. Deng, P. Zanzonico, Q. Chen, R. Finn, C. Ling, G. C. Li

Memorial Sloan-Kettering Cancer Center, New York, NY

Purpose/Objective(s): Tumor hypoxia, found in many human cancers, leads to radio- and chemo-resistance, a more aggressivephenotype, and is of prognostic value for treatment outcome. Assays of tumor hypoxia could provide useful data for designinghypoxia-targeted radiation treatments. The goal of this study is to evaluate a human tumor xenograft model for noninvasiveimaging of hypoxia-induced gene expression.

Materials/Methods: We have recently established human colorectal cancer cell lines (HCT8-HRE) which contain a hypoxia-inducible dual reporter: the herpes simplex virus type 1 - thymidine kinase and the enhanced green fluorescent protein(designated as tkeGFP). In transplanted xenografts in nude mice, the hypoxia-induced upregulation of HIF-1 will lead toexpression of the tkeGFP fusion gene, which can be assessed by the HSV1-tk mediated phosphorylation and trapping of the124I-FIAU reporter substrate. MicroPET and digital autoradiography (DAR) were used to visualize the 124I-FIAU distribution,as a surrogate of hypoxia-induced molecular events. The distribution of the 124I-FIAU (the endogenous marker) was thencompared with those of exogenous hypoxia cell markers: 18F-FMISO (using microPET and DAR) and pimonidazole (usingimmunohistochemistry (IHC)).

Results: For the HCT8-HRE cell lines, the hypoxic inducibility of the tkeGFP fusion gene was verified in vitro by fluorescentmicroscopy, flow cytometry, and 14C-FIAU accumulation. For transplanted xenografts, microPET images showed accumula-tion of 124I-FIAU in HCT8-HRE tumors, but not in HCT-8 parental tumors. Furthermore, the intratumoral distributions of124I-FIAU and 18F-FMISO, as assessed by microPET imaging, are qualitatively similar. In tumor sections, DAR and IHCanalysis show similarity in the distributions of 124I-FIAU, 18F-FMISO and pimonidazole.

Conclusions: A tumor hypoxia model of human colorectal carcinoma has been developed and characterized. This is the firsthuman tumor model that allows the detection of hypoxia-induced molecular events and the mapping of their distribution in vivowith noninvasive PET imaging and high-resolution DAR. This model provides a link between hypoxia-induced molecularevents and the use of exogenous hypoxia markers, e.g. pimonidazole.

Author Disclosure: F. He, None; Y. Huang, None; B. Wen, None; X. Deng, None; P. Zanzonico, None; Q. Chen, None; R. Finn,None; C. Ling, None; G.C. Li, None.

2631 Penetration and Retention of Intracavitary Administered I-131-TM-601 Peptide in Patients WithRecurrent High-Grade Glioma

S. Shen1, A. Mamelak2, S. Rosenfeld3, R. Bucholz4, A. Raubitschek5, L. Nabors3, J. Fiveash1, M. Khazaeli1, A. Liu5,V. Alvarez6

1Radiation Oncology, University of Alabama, Birmingham, AL, 2Oncological Surgery, City of Hope Nat Med Center,Duarte, CA, 3Neurology, University of Alabama, Birmingham, AL, 4Neurosurgery, Saint Louis University, St. Louis, MO,5Radioimmunotherapy, City of Hope Nat Med Center, Duarte, CA, 6TransMolecular, Inc., Birmingham, AL

Purpose/Objective(s): Clinical trials with intracranial administered radiolabeled antibodies have been promising because ittailors the dose distribution to the target volume and avoids a second invasive procedure compared to traditional solid sourceimplants. One limitation of that approach is that antibody is confined within the surgically created tumor cavity because ofrelatively large molecular size. TM-601 is a peptide derived from the venom of the scorpion that specifically binds to malignantbrain tumors. Because of its small size, it is possible to penetrate tumor cavity wall and deliver localized radiation to residualtumor cells. This study evaluates penetration and retention of I-131-TM-601 in tumor cavity in patients with recurrenthigh-grade glioma.

Materials/Methods: TM-601, or Chlorotoxin, (TransMolecular, Inc. Birmingham, AL) is a, 36 amino acid, peptide derivedfrom the venom of the scorpion Leiurus Quinquestriatus. 18 patients received single injection of 10 mCi I-131-TM-601 intotumor cavities via a ventriculostomy reservoir device. At immediate and up to 168 hr post injection, sequential 5 whole bodyand 5 SPECT images were acquired for I-131 quantification in normal organs and tumor cavity region. Attenuation correctionfor geometric-mean quantification was determined using Co-57 transmission scan. Blood samples were collected 1, 2, 4, 24,48, 72 and between 120–168 hours post injection. Cumulated radioactivity in urine were collected every 24 hour interval.Postoperative MRI scans were acquired for each patient prior to I-131-TM-601 injection, and at three and six months afterinjection.

S560 I. J. Radiation Oncology ● Biology ● Physics Volume 66, Number 3, Supplement, 2006