Despite continued improvements in diagnosis, surgical techniques, and radiation protocols, the available treatments for high-grade malignant glioma are grossly inadequate. The median survival time for most patients with high-grade gliomas is on the order of months. Because surgery is the only therapy currently available that provides some benefit for these patients, the development of a potent adjuvant to surgery could indeed tip the balance towards a better outcome. The most common and malignant brain tumor, glioblastoma multiforme, is characterized by the presence of necrosis, vascular proliferation, and aggressive invasion into surrounding normal brain tissue. Although the specific mechanisms facilitating the invasive behaviors of brain cancer are unclear, tumor cell invasion are known to be mediated, at least in part, through degradation of basement membrane by neutral metalloproteinases (MMP) produced by tumor cells and stroma cells. Evidence suggests that MMP-2 and MMP-9 play a significant role in CNS tumor cell invasion and metastasis. Recently, we have shown that DNAzyme generated against either MMP-2 or MMP-9 mRNA was able to reduce the expression of the enzymes in vitro, as well as the size of the C6-glioma generated in the in vivo animal model. Given their potential for systemic administration and targeting, DNAzymes could prove useful as a therapy against Glioma invasion by targeting MMPs. Toward achievement of this goal, 1. the minimum effective dose of DNAzyme needed to completely eradicate the tumor without causing significant toxicity to the surrounding healthy tissue of the brain will be determined by a dose escalation and a time course study of DNAzyme in the rat intracranial glioma model. We will simultaneously evaluate the safety and bioavailability of DNAzymes in healthy CNS tissues. 2. the efficacy of DNAzyme in treating human glioma will be tested in rat xenograft intracranial glioma model. And, 3. the effect of DNAzymes treatment on life expectancy (survival rate) of the animals bearing glioma will be assessed. Thus, in this proposal we are taking an innovative approach to the treatment of glioma by studying the effect the anti MMP-2 and MMP-9 DNAzymes therapy on the major mechanism of morbidity and mortality. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Developmental Therapeutics Study Section (DT)
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Yovandich, Jason L
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University of Tennessee Health Science Center
Other Basic Sciences
Schools of Medicine
United States
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Hallett, Miranda A; Teng, Bin; Hasegawa, Hisashi et al. (2013) Anti-matrix metalloproteinase-9 DNAzyme decreases tumor growth in the MMTV-PyMT mouse model of breast cancer. Breast Cancer Res 15:R12
Hallett, Miranda A; Dalal, Pooja; Sweatman, Trevor W et al. (2013) The distribution, clearance, and safety of an anti-MMP-9 DNAzyme in normal and MMTV-PyMT transgenic mice. Nucleic Acid Ther 23:379-88
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