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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107183-05
Application #
7622087
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Yovandich, Jason L
Project Start
2005-08-17
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2009
Total Cost
$246,068
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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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
Fasciglione, Giovanni Francesco; Gioia, Magda; Tsukada, Hiroki et al. (2012) The collagenolytic action of MMP-1 is regulated by the interaction between the catalytic domain and the hinge region. J Biol Inorg Chem 17:663-72
Tochowicz, Anna; Maskos, Klaus; Huber, Robert et al. (2007) Crystal structures of MMP-9 complexes with five inhibitors: contribution of the flexible Arg424 side-chain to selectivity. J Mol Biol 371:989-1006
O'Farrell, Thomas J; Guo, Rong; Hasegawa, Hisashi et al. (2006) Matrix metalloproteinase-1 takes advantage of the induced fit mechanism to cleave the triple-helical type I collagen molecule. Biochemistry 45:15411-8