Yang M.Y.,U.S. National Cancer Institute |
Chaudhary A.,U.S. National Cancer Institute |
Seaman S.,U.S. National Cancer Institute |
Dunty J.,U.S. National Cancer Institute |
And 4 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2011
Tumor endothelial marker 8 (TEM8) is an integrin-like cell surface protein upregulated on tumor blood vessels and a potential vascular target for cancer therapy. Here, we found that the ability of an anti-TEM8 antibody, clone SB5, to recognize the extracellular domain of TEM8 on the cell surface depends on other host-cell factors. By taking advantage of SB5's ability to distinguish different forms of cell surface TEM8, we identified alpha-smooth muscle actin and transgelin, an actin binding protein, as intracellular factors able to alter TEM8 cell surface structure. Overexpression of either of these proteins in cells converted TEM8 from an SB5-exposed to an SB5-masked form and protected cells from SB5-saporin immunotoxins. Because the predominant form of TEM8 on the cell surface is not recognized by SB5, we also developed a new monoclonal antibody, called AF334, which is able to recognize both the SB5-exposed and the SB5-masked forms of TEM8. AF334-saporin selectively killed TEM8-positive cells independent of TEM8 cell surface structure. These studies reveal that TEM8 exists in different forms at the cell surface, a structure dependent on interactions with components of the actin cytoskeleton, and should aid in the rational design of the most effective diagnostic and therapeutic anti-TEM8 monoclonal antibodies. © 2010.
Mauldin J.P.,Scott and White Cancer Research Institute |
Zeinali I.,Scott and White Cancer Research Institute |
Kleypas K.,Scott and White Cancer Research Institute |
Woo J.H.,Scott and White Cancer Research Institute |
And 5 more authors.
Translational Oncology | Year: 2012
Human recombinant arginase I cobalt coupled to polyethylene glycol 5000 (HuArg I [Co]-PEG5000) achieved potent in vitro depletion of arginine from tissue culture medium and cytotoxicity to many cancer cell lines. The recombinant enzyme also produced tumor growth inhibition of hepatocellular carcinoma and pancreatic carcinoma xenografts. Although these results were promising, the therapeutic index was narrow. Toxicities were seen in normal cells in tissue culture. In vivo normal tissue injury occurred at doses twice the effective dose. The current study was conducted to define, in greater detail, the maximum tolerated dose (MTD), pharmacodynamics, and doselimiting toxicities (DLTs) of twice-weekly intraperitoneal HuArg I [Co]-PEG5000 in Balb/c mice. Animal weight and survival were monitored, serum arginine levels measured, and complete blood cell counts, chemistries, necropsies, and histologies were performed. In addition, methods to ameliorate the HuArg I [Co]-PEG5000 adverse effects were tested. Supplemental L-citrulline was given concurrently with the arginase drug. The HuArg I [Co]-PEG5000 MTD in mice was 5 mg/kg twice weekly, and DLTs included weight loss and marrow necrosis. No other organ damage or changes in blood cell counts or chemistries were observed. Arginase reduced serum arginine levels from 60 μM to 4 to 6 μM. Supplemental L-citrulline given per os or daily subcutaneously reduced and delayed toxicities, and L-citrulline given twice daily subcutaneously completely prevented animal toxicities. On the basis of these results, we hypothesize that HuArg I [Co]-PEG5000, particularly with supplemental L-citrulline, may be an attractive therapeutic agent for argininosuccinate synthetase-deficient tumors. © 2012 Neoplasia Press, Inc. All rights reserved.
Yoon J.-K.,University of Houston |
Yoon J.-K.,Hwasung Public Health Center |
Frankel A.E.,Scott and White Cancer Research Institute |
Feun L.G.,University of Miami |
And 2 more authors.
Clinical Pharmacology: Advances and Applications | Year: 2012
Despite recent development of promising immunotherapeutic and targeted drugs, prognosis in patients with advanced melanoma remains poor, and a cure for this disease remains elusive in most patients. The success of melanoma therapy depends on a better understanding of the biology of melanoma and development of drugs that effectively target the relevant genes or proteins essential for tumor cell survival. Melanoma cells frequently lack argininosuccinate synthetase, an essential enzyme for arginine synthesis, and as a result they become dependent on the availability of exogenous arginine. Accordingly, a therapeutic approach involving depletion of available arginine has been shown to be effective in preclinical studies. Early clinical studies have demonstrated sufficient antitumor activity to give rise to cautious optimism. In this article, the rationale for arginine deprivation therapy is discussed. Additionally, various strategies for depleting arginine are discussed and the preclinical and clinical investigations of arginine deprivation therapy in melanoma are reviewed. © 2013 Yoon et al, publisher and licensee Dove Medical Press Ltd.
Agrawal V.,Scott and White Cancer Research Institute |
Woo J.H.,Scott and White Cancer Research Institute |
Borthakur G.,University of Texas M. D. Anderson Cancer Center |
Kantarjian H.,University of Texas M. D. Anderson Cancer Center |
Frankel A.E.,Scott and White Cancer Research Institute
Protein and Peptide Letters | Year: 2013
Red blood cell (RBC) encapsulated L-asparaginase is a novel therapeutic for the treatment of asparagine auxotrophic malignancies. The enzyme-loaded red blood cells function as bioreactors to deplete bloodstream substrate. This delivery system provides improved pharmacodynamics with protection from circulating proteolytic enzymes and avoidance of early liver or renal clearance. The drug is manufactured with ABO and Rh compatible donor blood when a prescription is received. Because of the industrial scale manufacturing, the drug is transfused the day of receipt at the clinical site. Preliminary clinical studies show utility in childhood and adult acute lymphoblastic leukemia. Based on previous studies of applications in different diseases and assessment of different biomarkers, we propose this agent offers a safe and potentially effective treatment for a subset of chemotherapy refractory acute myeloid leukemia patients. The history, chemistry, biology, pharmacology, and relevant clinical experiences with L-asparaginase as well as the properties and proposed protocols with the red cell-encapsulated enzyme are reviewed. © 2013 Bentham Science Publishers.