Abstract
Expression of chemokine receptors by tumors, specifically CCR4 on cutaneous T cell lymphomas, is often associated with a poor disease outcome. To test the hypothesis that chemokine receptor-expressing tumors can be successfully controlled by delivering toxins through their chemokine receptors, we have generated fusion proteins designated chemotoxins: chemokines fused with toxic moieties that are nontoxic unless delivered into the cell cytosol. We demonstrate that chemokines fused with human RNase eosinophil-derived neurotoxin or with a truncated fragment of Pseudomonas exotoxin 38 are able to specifically kill tumors in vitro upon internalization through their respective chemokine receptors. Moreover, treatment with the thymus and activation-regulated chemokine (CCL17)-expressing chemotoxin efficiently eradicated CCR4-expressing cutaneous T cell lymphoma/leukemia established in NOD-SCID mice. Taken together, this work represents a novel concept that may allow control of growth and dissemination of tumors that use chemokine receptors to metastasize and circumvent immunosurveillance.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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ADP Ribose Transferases / genetics
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ADP Ribose Transferases / toxicity
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / toxicity*
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Bacterial Toxins / genetics
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Bacterial Toxins / toxicity
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Cell Death / genetics
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Cell Death / immunology
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Cell Line
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Cell Line, Tumor
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Chemokine CCL17
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Chemokines, CC / administration & dosage
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Chemokines, CC / genetics
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Chemokines, CC / toxicity
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Cytotoxicity, Immunologic* / genetics
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Eosinophil-Derived Neurotoxin / genetics
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Eosinophil-Derived Neurotoxin / toxicity
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Exotoxins / genetics
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Exotoxins / toxicity
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Female
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Humans
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Immunotoxins / genetics
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Immunotoxins / toxicity*
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Leukemia-Lymphoma, Adult T-Cell / immunology*
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Leukemia-Lymphoma, Adult T-Cell / metabolism
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Leukemia-Lymphoma, Adult T-Cell / pathology
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Leukemia-Lymphoma, Adult T-Cell / therapy*
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Recurrence, Local
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Pseudomonas aeruginosa Exotoxin A
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Receptors, CCR4
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Receptors, Chemokine / biosynthesis
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Receptors, Chemokine / metabolism*
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Viral Proteins / genetics
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Viral Proteins / toxicity
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Virulence Factors / genetics
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Virulence Factors / toxicity
Substances
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Antineoplastic Agents
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Bacterial Toxins
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CCR4 protein, human
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Ccl17 protein, mouse
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Ccr4 protein, mouse
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Chemokine CCL17
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Chemokines, CC
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Exotoxins
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Immunotoxins
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MC148 protein, poxvirus molluscum contagiosum
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Receptors, CCR4
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Receptors, Chemokine
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Viral Proteins
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Virulence Factors
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ADP Ribose Transferases
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Eosinophil-Derived Neurotoxin