Efficacy of the matrix metalloproteinase-activated anthrax lethal toxin in the treatment of solid tumors : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2009]
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| Subjects: |
| Abstract: | ABSTRACT: Current efforts in the design of novel cancer therapeutics have focused on explicitly targeting tumor cells via upregulated markers or pathways that are significant in neoplastic progression. The mitogen-activated protein kinase (MAPK) pathways are critical in normal cell proliferation, survival and differentiation. These pathways present a rich source of oncogenic events in cellular transformation. Mutations leading to the constitutive MAPK activation have been shown to occur in solid tumors. A specific valine to glutamic acid substitution at amino acid position 600 of the B-Raf protein component constitutively activates this pathway, resulting in loss of cell proliferation control. SImilarly, expression of the matrix metalloproteinases (MMPs) have been shown to be critical tumor cell invasion, metastasis, and tumor-mediated angiogenesis. The explicit targeting of these 2 tumor markers may provide a novel therapeutic strategy for the treatment of solid tumors. Anthrax Lethal toxin (LeTx) has potent MAPk inhibition activity and is selectivity cytotoxic to tumor cells harboring the V600E B-Raf mutation. Consisting of Protective Antigen (PA) and Lethal Factor (LF), LeTx action is dependent on the proteolytic cleavage of PA by host cell surface furin or furin-like proteases. Due to the ubiquitous expression of these proteases, half life of LeTx is extremely short, thus compromising anti-tumor efficacy. Modification of the PA furin activation sequence to a substrate preferably cleaved by gelatinases (MMP-2/-9) produced a recombinant gelatinase-activated PA, designated PA-L1, with improved plasma half life. Our studies demonstrate the enhanced selectivity of this novel toxin in that PA-L1/LF is cytotoxic only to tumor cells that both express MMPs as well as harbor the V600E B-Raf mutation. Further, we demonstrate that PA-L1/LF treatment of microvascular endothelial cells induces a paralytic-like response. PA-L/LF-treated microvascular endothelial cells exhibit a reduced paralytic-like response. PA-L1/LF-treated microvascular endothelial cells exhibit a reduced migratory and invasive capacity, leading to the failure of tube formation in vitro. This reduced ability to both migrate and degrade extracellular matrix translates to potent tumor-mediated angiogenesis inhibition in vivo, and thus broad anti-tumor activity. Thus, the primary anti-tumor mechanism of PA-L1/LF is the inhibition of tumor-mediated angiogenesis. These results indicate the potential clinical application of the PA-L1/LF in the treatment of solid tumors. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2009." Approved as to style and content by: Arthur E. Frankel, Jung Hee Woo, Cynthia J. Meininger, Alexzander Asea . |
| Physical Description: | xiii, 159 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 154-156). |