Targeting the arginine auxotrophic nature of cancer utilizing a novel human recombinant arginase [Co]-PEG5000 (CoArgIPEG) : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M Health Science Center],
[2013]
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| Subjects: |
| Abstract: | ABSTRACT: A number of cancers are auxotrophic or dependent on extracellular sources of L-arginine for survival. Depletion of extracellular L-arginine has been accomplished by dietary restriction and enzyme therapy including pegylated recombinant arginine deiminase, pegylated recombinant human arginase I, and pegylated cobalt substituted recombinant human arginase I (Co-ArgI-PEG). We tested the latter on tumor and normal cell lines in the presence and absence of L-citrulline and correlated sensitivity with levels of argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC) expression.We assessed proliferation inhibition, protein synthesis inhibition and metabolic viability post-CoArgIPEG treatment both in the presence and absence of citrulline. Sensitivity was correlated to ASS and OTC expression. In the presence of supplemental citrulline, Co-ArgI-PEG was cytotoxic to tumors lacking ASS but not normal cells. Toxicity was alleviated in the presence of supplemental citrulline. We further developed an NSG mouse model of A375 melanoma cells, an ASS-negative cancer. We treated mice at the maximum tolerated dose (MTD) of Co-ArgI-PEG in the presence or absence of citrulline. Dramatic tumor growth inhibition was observed. After one month, half of the relapsing tumors showed ASS induction. ASS induction was found to correlate with ser62-phosphorylated c-Myc. Although ASS induction could not be induced in vitro, a drug targeting pathways previously demonstrated to be associated with ser62 cMyc phosphorylation, U0126, in combination with CoArgIPEG, demonstrated an in vitro synergistic response. Co-ArgI-PEG has been produced under current good manufacturing practices (cGMP) and places in clinically applicable drug vials for administration. Quality control tests are ongoing. GLP pharmacology/toxicology in mice has been initiated. Phase I clinical studies with Co-ArgI-PEG in solid tumor patients that are ASS negative should begin soon. |
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| Item Description: | Vita. "Major Subject: Biomedical Science". "Submitted to The Office of Research and Graduate Studies of The Texas A&M Health Science Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2013." Approved as to style and content by: Arthur E. Frankel, Cynthia J. Meininger, Everett M. Stone, Alejandro C. Arroliga. |
| Physical Description: | xvi, 146 leaves : illustrations ; 29 cm. |
| Bibliography: | Includes bibliographical references (leaves 28-36, 72-78, 98-101,126-129, 140-144). |