The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Raj K. Puri - One of the best experts on this subject based on the ideXlab platform.
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interleukin 4 Cytotoxin therapy synergizes with gemcitabine in a mouse model of pancreatic ductal adenocarcinoma
Cancer Research, 2007Co-Authors: Takeshi Shimamura, Mitomu Kioi, Syed R. Husain, Richard E Royal, Atsushi Nakajima, Raj K. PuriAbstract:Targeting cell surface receptors with Cytotoxins or immunotoxins provides a unique opportunity for tumor therapy. Here, we show the efficacy of the combination therapy of gemcitabine with an interleukin-4 (IL-4) Cytotoxin composed of IL-4 and truncated Pseudomonas exotoxin in animal models of pancreatic ductal adenocarcinoma (PDA). We have observed that 42 of 70 (60%) tumor samples from patients with PDA express moderate- to high-density surface IL-4 receptor (IL-4R), whereas normal pancreatic samples express no or low-density IL-4R. IL-4 Cytotoxin was specifically and highly cytotoxic [50% protein synthesis inhibition (IC50) ranging from >0.1 to 13 ng/mL] to six of eight pancreatic cancer cell lines, whereas no cytotoxicity (IC50>1,000 ng/mL) was observed in normal human pancreatic duct epithelium cells, fibroblasts, and human umbilical vein endothelial cells (HUVEC). We also showed that IL-4 Cytotoxin in combination with gemcitabine exhibited synergistic antitumor activity in vitro. To confirm synergistic antitumor activity in vivo and monitor precise real-time disease progression, we used a novel metastatic and orthotopic mouse model using green fluorescent protein-transfected cancer cells and whole-body imaging system. The combination of both agents caused complete eradication of tumors in 40% of nude mice with small established PDA tumors. In addition, combined treatment significantly prolonged the survival of nude mice bearing day 14 advanced distant metastatic PDA tumors. Similar results were observed in mice xenografted with PDA obtained from a patient undergoing surgical resection. These results indicate that IL-4 Cytotoxin combined with gemcitabine may provide effective therapy for the treatment of patients with PDA.
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interleukin 13 receptor α2 chain
Cancer, 2006Co-Authors: Mitomu Kioi, Mariko Kawakami, Takeshi Shimamura, Syed R. Husain, Raj K. PuriAbstract:BACKGROUND Epithelial ovarian cancer demonstrates high mortality due to diagnosis at an advanced stage. In the search for a biomarker for early diagnosis and a target for therapy, the issue of whether interleukin-13 receptor (IL-13R), shown to be expressed on a variety of human cancers, is expressed in ovarian tumor samples was explored. In addition, whether this receptor serves as a biomarker and can be targeted by IL-13 Cytotoxin was examined. METHODS IL-13R expression in 15 normal and 68 ovarian tumor tissue samples was determined by immunohistochemistry. Correlation between clinicopathologic features and IL-13R expression was analyzed. The efficacy of IL-13R-directed Cytotoxin was determined in mice with subcutaneous, orthotopic, and peritoneal metastatic ovarian cancer. RESULTS Immunohistochemical analyses revealed that 83% of ovarian cancer specimens express IL-13Rα2, a high-affinity IL-13R subunit chain, whereas normal ovary samples expressed none or very low levels. The majority of clear cell ovarian carcinomas with the worst prognosis showed strong staining for IL-13Rα2. IL-13 Cytotoxin was highly cytotoxic to the IGROV-1 ovarian cancer cell line in vitro, and it mediated significant antitumor activity against a xenografted tumor model. The antitumor effects were confirmed by treating orthotopically implanted or peritoneal metastatic ovarian tumors, which showed significant extension of survival in immunodeficient mice. IL-13 Cytotoxin also prevented cachexia in treated mice. The soluble form of IL-13Rα2 was detected in the serum of mice with peritoneal metastasis, and the level decreased to baseline in the treated group. CONCLUSIONS IL-13Rα2 is a promising target for ovarian cancer therapy, and the soluble form of IL-13R may be a possible surrogate marker for disease monitoring. Cancer. Published 2006 by the American Cancer Society.
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Interleukin-13 receptor-directed Cytotoxin for malignant glioma therapy: from bench to bedside.
Journal of neuro-oncology, 2003Co-Authors: Syed R. Husain, Raj K. PuriAbstract:Central nervous system malignant neoplasias, in particular, glioblastoma multiforme (GBM) have defied all current therapeutic modalities. New therapies involving tumor targeting approach are being explored. This approach relies on the identification of unique or over-expressed cell surface receptors or antigens on tumor cells. In that regard, we have identified receptor for an immune regulatory cytokine, interleukin-13 (IL-13), which is over-expressed on human malignant glioma cell lines and primary tumor cell cultures. To target IL-13 receptors (IL-13R) for cancer therapy, we have developed a recombinant fusion protein composed of IL-13 and a mutated form of Pseudomonas exotoxin (IL13-PE38QQR or IL-13 Cytotoxin). The IL-13 Cytotoxin was found to be highly selective and potent in killing human GBM cells in vitro while normal cells including immune cells, endothelial cells and normal brain cells were generally spared the cytotoxic effect of IL-13 Cytotoxin. This is because these cells either expressed none or expressed low levels of IL-13R. Consistent with in vitro cytotoxic activity, IL-13 Cytotoxin mediated remarkable anti-tumor activity to human glioma in animal xenograft models. The direct injection of IL-13 Cytotoxin into subcutaneous human GBM tumors grown in nude mice produced complete and durable regression of established tumors. Intravenous and intraperitoneal administration of IL-13 Cytotoxin also reduced tumor burden significantly with fewer complete responders. All animals tolerated therapy well with minimal toxicity to vital organs. Pre-clinical safety and toxicity studies were performed in mice, rats and monkeys. Systemic administration of IL-13 Cytotoxin appeared to be well tolerated at high doses (up to 50 microg/kg). Intrabrain parenchyma administration of IL-13 Cytotoxin at doses up to 100 microg/ml was very well tolerated without any evidence of gross or microscopic necrosis, whereas at 500 microg/ml dose, localized necrosis was observed in normal rat brain. Based on these encouraging pre-clinical studies, three Phase I/II clinical trials in adults with malignant glioma have been initiated. The first clinical trial involves convection-enhanced delivery (CED) of IL-13 Cytotoxin into recurrent malignant glioma. This route of IL-13 Cytotoxin administration appears to be fairly well tolerated with no neurotoxicity. The second clinical trial involves infusion of IL-13 Cytotoxin by CED following tumor resection. The initial stage of the second study assessed histologic effect of drug administered prior to resection. In third one, IL-13 Cytotoxin is infused by CED followed by tumor resection. All three clinical trials are currently ongoing.
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Intratumor administration of interleukin 13 receptor-targeted Cytotoxin induces apoptotic cell death in human malignant glioma tumor xenografts.
Molecular cancer therapeutics, 2002Co-Authors: Mariko Kawakami, Koji Kawakami, Raj K. PuriAbstract:Apoptosis is not only essential for homeostasis in normal cells but also in cancer cells, in which it is associated with cell death mechanisms caused by novel therapeutics. We have previously reported that interleukin-13 receptors (IL-13R) are constitutively overexpressed on a majority of human malignant glioma cell lines and primary cell cultures. In addition, we have reported that IL-13 Cytotoxin, comprised of human IL-13 and a mutated form of Pseudomonas exotoxin, is highly and specifically cytotoxic to these cells and can lead to pronounced antitumor activity in malignant glioma tumors in animal models. However, the molecular mechanisms of tumor cytotoxicity induced by IL-13 Cytotoxin are poorly understood. In this study, we demonstrate that glioma tumors undergo apoptotic cell death on intratumoral administration of IL-13 Cytotoxin. This conclusion was made based on (a) time-dependent induction of several proapoptotic molecules, such as caspases (caspase-3, -8, and -9) in tumors; (b) cleavage of procaspase-3 and poly(ADP-ribose) polymerase (PARP); and (c) the release of cytochrome c from mitochondria to the cytosol on injection of IL-13 Cytotoxin in U251 glioblastoma tumors established in immunodeficient animals. These indicators of two major pathways of apoptosis were detected in tumors even though IL-13 Cytotoxin was no longer present in tumors. In addition, we found that inducible nitric oxide was expressed in tumors in a time-dependent manner with primary localization in infiltrating phagocytes after treatment with IL-13 Cytotoxin. These studies demonstrate that IL-13 Cytotoxin mediates apoptotic death of glioma cells, resulting in regression of established tumors. Our studies will help unravel the molecular pathways of cell death associated with tumor regression and provide additional insight and define apoptosis as possible surrogate marker of tumor response.
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suppression of an il 13 autocrine growth loop in a human hodgkin reed sternberg tumor cell line by a novel il 13 antagonist
Cellular Immunology, 2001Co-Authors: Yasuo Oshima, Raj K. PuriAbstract:Abstract IL-13 has been proposed to be an autocrine growth factor for Hodgkin/Reed-Sternberg tumor cells (H/RS cells). Since we have recently identified and produced a novel IL-13 antagonist (IL-13E13K) that can suppress the biological activity of IL-13, here we examined whether IL-13E13K can inhibit growth of Hodgkin lymphoma (HL)-derived cell lines. IL-13E13K not only inhibited the growth of an unstimulated H/RS cell line (L1236) but also cells that were stimulated by exogenous IL-13 in a dose-dependent manner. Several HL-derived cell lines expressed IL-13 message and protein and message for various chains of IL-13R. H/RS cell lines expressed mRNA for the IL-13Rα1, IL-4Rα, and IL-2Rγ chains. However, none of these cell lines expressed the IL-13Rα2 chain. An H/RS cell line (L1236) internalized the ligand–receptor complex after binding to a fusion protein composed of IL-13 and a mutated form of Pseudomonas exotoxin A (IL-13-PE38QQR, or IL-13 Cytotoxin), as IL-13 Cytotoxin was specifically cytotoxic to H/RS cells in vitro. These results indicate that IL-13E13K and IL-13 Cytotoxin can effectively suppress growth of a L1236 H/RS cell line. Therefore, additional studies should be performed to determine the expression of IL-13 and IL-13R in primary clinical samples of Hodgkin's lymphoma and both agents should be further tested in vitro and in vivo as possible therapeutic agents for HL.
Ronald T. Raines - One of the best experts on this subject based on the ideXlab platform.
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a human ribonuclease variant and erk pathway inhibitors exhibit highly synergistic toxicity for cancer cells
Molecular Cancer Therapeutics, 2018Co-Authors: Trish T Hoang, Ronald T. Raines, Caglar I Tanrikulu, Quinn A Vatland, Trieu M HoangAbstract:Pancreatic-type ribonucleases (ptRNases) are prevalent secretory enzymes that catalyze the cleavage of RNA. Ribonuclease inhibitor (RI) is a cytosolic protein that has femtomolar affinity for ptRNases, affording protection from the toxic catalytic activity of ptRNases, which can invade human cells. A human ptRNase variant that is resistant to inhibition by RI is a Cytotoxin that is undergoing a clinical trial as a cancer chemotherapeutic agent. We find that the ptRNase and protein kinases in the ERK pathway exhibit strongly synergistic toxicity toward lung cancer cells (including a KRASG12C variant) and melanoma cells (including BRAFV600E variants). The synergism arises from inhibiting the phosphorylation of RI and thereby diminishing its affinity for the ptRNase. These findings link seemingly unrelated cellular processes, and suggest that the use of a kinase inhibitor to unleash a cytotoxic enzyme could lead to beneficial manifestations in the clinic.
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human angiogenin is a potent Cytotoxin in the absence of ribonuclease inhibitor
RNA, 2018Co-Authors: Sydney P Thomas, Trish T Hoang, Valerie T Ressler, Ronald T. RainesAbstract:Angiogenin (ANG) is a secretory ribonuclease that promotes the proliferation of endothelial cells, leading to angiogenesis. This function relies on its ribonucleolytic activity, which is low for simple RNA substrates. Upon entry into the cytosol, ANG is sequestered by the ribonuclease inhibitor protein (RNH1). We find that ANG is a potent Cytotoxin for RNH1-knockout HeLa cells, belying its inefficiency as a nonspecific catalyst. The toxicity does, however, rely on the ribonucleolytic activity of ANG and a cytosolic localization, which lead to the accumulation of particular tRNA fragments (tRFs), such as tRF-5 Gly-GCC. These up-regulated tRFs are highly cytotoxic at physiological concentrations. Although ANG is well-known for its promotion of cell growth, our results reveal that ANG can also cause cell death.
Frederic Taieb - One of the best experts on this subject based on the ideXlab platform.
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corrigendum heterogeneous family of cyclomodulins smart weapons that allow bacteria to hijack the eukaryotic cell cycle and promote infections
Frontiers in Cellular and Infection Microbiology, 2017Co-Authors: Martine Deplanche, Frederic Taieb, Pierre L Goossens, Thiago Luiz De Paula Castro, Gérard Lina, Aurélie Nicolas, Rachid Elaouar Filho, Vasco Azevedo, Yves Le LoirAbstract:Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of action of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating Cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leucocidin, phenol soluble modulins and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host.
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Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections
Frontiers in Cellular and Infection Microbiology, 2017Co-Authors: Rachid A. El-aouar Filho, Martine Deplanche, Vasco A. De Carvalho Azevedo, Frederic Taieb, Pierre L Goossens, Thiago Luiz De Paula Castro, Gérard Lina, Aurélie Nicolas, Yves Le Loir, Nadia BerkovaAbstract:Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of actions of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating Cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leukocidin, phenol soluble modulins, and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host.
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bacterial toxins that modulate host cell cycle progression
Current Opinion in Microbiology, 2005Co-Authors: Eric Oswald, Frederic Taieb, Jeanphilippe Nougayrede, Motoyuki SugaiAbstract:The mammalian cell cycle is involved in many processes — such as immune responses, maintenance of epithelial barrier functions, and cellular differentiation — that affect the growth and colonization of pathogenic bacteria. Therefore it is not surprising that many bacterial pathogens manipulate the host cell cycle with respect to these functions. Cyclomodulins are a growing family of bacterial toxins and effectors that interfere with the eukaryotic cell cycle. Here, we review some of these cyclomodulins such as cytolethal distending toxins, vacuolating Cytotoxin, the polyketide-derived macrolide mycolactone, cycle-inhibiting factor, cytotoxic necrotizing factors, dermonecrotic toxin, Pasteurella multocida toxin and Cytotoxin-associated antigen A. We describe and compare their effects on the mammalian cell cycle and their putative role in disease, commensalism and symbiosis. We also discuss a possible link between these cyclomodulins and cancer.
Yves Le Loir - One of the best experts on this subject based on the ideXlab platform.
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corrigendum heterogeneous family of cyclomodulins smart weapons that allow bacteria to hijack the eukaryotic cell cycle and promote infections
Frontiers in Cellular and Infection Microbiology, 2017Co-Authors: Martine Deplanche, Frederic Taieb, Pierre L Goossens, Thiago Luiz De Paula Castro, Gérard Lina, Aurélie Nicolas, Rachid Elaouar Filho, Vasco Azevedo, Yves Le LoirAbstract:Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of action of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating Cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leucocidin, phenol soluble modulins and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host.
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Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections
Frontiers in Cellular and Infection Microbiology, 2017Co-Authors: Rachid A. El-aouar Filho, Martine Deplanche, Vasco A. De Carvalho Azevedo, Frederic Taieb, Pierre L Goossens, Thiago Luiz De Paula Castro, Gérard Lina, Aurélie Nicolas, Yves Le Loir, Nadia BerkovaAbstract:Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of actions of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating Cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leukocidin, phenol soluble modulins, and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host.
Waldemar Debinski - One of the best experts on this subject based on the ideXlab platform.
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reoxygenation of hypoxic glioblastoma multiforme cells potentiates the killing effect of an interleukin 13 based Cytotoxin
Clinical Cancer Research, 2009Co-Authors: Denise M. Gibo, Waldemar DebinskiAbstract:Purpose: Hypoxia is a cause for resistance to cancer therapies. Molecularly targeted recombinant Cytotoxins have shown clinical efficacy in the treatment of patients with primary brain tumors, glioblastoma multiforme, but it is not known whether hypoxia influences their antitumor effect. Experimental Design: We have exposed glioblastoma multiforme cells, such as U-251 MG, U-373 MG, SNB-19, and A-172 MG, to either anoxia or hypoxia and then reoxygenated them while treating with an interleukin (IL)-13-based diphtheria toxin (DT)-containing Cytotoxin, DT-IL13QM. We measured the levels of immunoreactive IL-13Rα2, a receptor that mediates IL-13-Cytotoxin cell killing, and the levels of active form of furin, a protease that activates the bacterial toxin portion in a Cytotoxin. Results: We found that anoxia/hypoxia significantly alters the responsiveness of glioblastoma multiforme cells to DT-IL13QM. Interestingly, bringing these cells back to normoxia caused them to become even more susceptible to the Cytotoxin than the cells maintained under normoxia. Anoxia/hypoxia caused a highly prominent decrease in the immunoreactive levels of both IL-13R and active forms of furin, and reoxygenation not only restored their levels but also became higher than that in normoxic glioblastoma multiforme cells. Conclusions: Our results show that a recombinant Cytotoxin directed against glioblastoma multiforme cells kills these cells much less efficiently under anoxic/hypoxic conditions. The reoxygenation brings unexpected additional benefit of making glioblastoma multiforme cells even more responsive to the killing effect of a Cytotoxin.
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molecular targeting with recombinant Cytotoxins of interleukin 13 receptor α2 expressing glioma
Journal of Neuro-oncology, 2003Co-Authors: Akiva Mintz, A B Madhankumar, Denise M. Gibo, Waldemar DebinskiAbstract:A restricted receptor for interleukin 13 (IL-13R alpha2) is over-expressed in high-grade astrocytoma (HGA), but not in normal organs. In order to design and examine new anti-HGA therapies, which are molecularly directed against IL-13R alpha2, we established an IL-13R alpha2-expressing syngeneic immunocompetent murine model of HGA. The model was obtained by transfecting G-26 murine glioma cells with IL-13R alpha2. G-26-IL-13R alpha2(+) cells, but not mock-transfected cells, became susceptible to IL-13 mutant-based cytotoxic proteins that kill human HGA cells. G-26-IL-13R alpha2(+) cells maintained their tumorigenicity in immunocompetent C57BL/J6 mice and preserved their expression of IL-13R alpha2 in vivo. These characteristics of the G-26-IL-13R alpha2(+) tumors allowed us to test molecularly defined anti-glioma passive immunotherapy. A targeted recombinant chimera Cytotoxin composed of multiply mutated IL-13 (IL-13.E13Y/R66D/S69D) and a derivative of Pseudomonas exotoxin (PE), PE1E, IL-13.E13Y/R66D/S69D-PE1E, was used in anti-tumor experiments. G-26-IL-13R alpha2(+) cells were killed by IL-13.E13Y/R66D/S69D-PE1E in an IL-4-independent fashion. To test the Cytotoxin in vivo, G-26-IL-13R alpha2(+) tumors were established in C57BL/J6 mice and when the tumors reached a size of at least 50 mm3, the mice were treated with IL-13.E13Y/R66D/S69D-PE1E. In the mice treated with the targeted fusion Cytotoxin, the tumors regressed and 80% of the animals were cured. This study documents the establishment of an IL-13R alpha2-positive model of HGA in immunocompetent rodents. Furthermore, the effectiveness and safety of the targeted IL-13-based Cytotoxin against IL-13R alpha2-expressing tumors in a more clinically relevant in vivo HGA model is promising with regard to the future clinical utility of the Cytotoxin.
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novel way to increase targeting specificity to a human glioblastoma associated receptor for interleukin 13
International Journal of Cancer, 1998Co-Authors: Waldemar Debinski, Denise M. Gibo, Raj K. PuriAbstract:Human brain cancers (gliomas) overexpress large numbers of a receptor for interleukin 13 (IL13), making this receptor an attractive target for anti-glioma therapies. We have recently proposed that the glioma-associated IL13 receptor is different from the one expressed on some hemopoietic and somatic cells. In an attempt to identify an even more glioma specific target, we have used an antagonist of a related cytokine, IL4, which neutralizes the physiological effects of both IL13 and IL4 on normal cells. Here we demonstrate that the IL4 antagonist also counteracts the action of Cytotoxins targeted to the IL13 receptor on normal human cells. Importantly, the IL4 antagonist does not inhibit IL13-based Cytotoxins on glioma cells at all. Thus, the IL13 receptor on glioma cells can be categorized as tumor-specific in the presence of an IL4 antagonist. We conclude that IL13 receptor-directed Cytotoxins can be delivered to glioma cells without being cytotoxic to normal cells.
