New therapeutic approach for brain tumors: intranasal delivery of telomerase inhibitor GRN163. Neuro Oncol

Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143-0520, USA.
Neuro-Oncology (Impact Factor: 5.29). 05/2008; 10(2):112-20. DOI: 10.1215/15228517-2007-052
Source: PubMed

ABSTRACT The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xenografts intranasally with GRN163, an oligonucleotide N3'-->P5'thio-phosphoramidate telomerase inhibitor. 3'-Fuorescein isothiocyanate (FITC)-labeled GRN163 was administered intranasally every 2 min as 6 microl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients.

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    • "The administration of [ 125 I]-labeled insulin-like growth factor-I ( 125 I-IGF-I) has been reported to increase levels of radioactivity in both the olfactory bulb and trigemininal ganglion of the rat brain, with the highest concentrations observed in the latter site (Thorne et al., 2004). In addition, the IN administration of various other products such as lidocaine, stem cells, and telomerase inhibitors have all been shown to reach the brainstem via trigeminal nerve fibers in rodents (Danielyan et al., 2011; Hashizume et al., 2008; Johnson et al., 2010), although it is possible that these substances reach the brainstem via other means such as diffusion though brain CSF via olfactory pathway entry. Notably, projections from the central amygdala and PVN extend to brainstem nuclei that regulate cardiovascular functioning (Viviani et al., 2011). "
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    • "Indeed, TERRA was recognized in vitro as a natural ligand and direct inhibitor of telomerase [41]. Direct inhibition of telomerase enzymatic activity has shown efficiency against glioma cell lines and xenografts [42] [43] [44], and first telomerase-based cancer therapy approaches are tested in clinical studies [45]. Thus, TERRA could be a further candidate for clinical prognosis, like O-methylguanine methyltransferase promoter methylation for alkylating agent in chemotherapy [35]. "
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    • "Recently, Doyle et al. (2008) 12 reported that the nasal administration of osteopontin peptide mimetics confers neuroprotection in rat stroke model, and Hashizume et al. (2008) 13 found that the intranasal delivery of an oligonucleotide telomerase inhibitor suppresses brain tumor growth and increased survival in rats. In addition, Danielyan et al. (2009) 14 reported the intranasal deliveries of mesenchymal stem cells and glioma cells to the rat brain. "
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