Critical role of indoleamine 2,3-dioxygenase in tumor resistance to repeated treatments with targeted IFNgamma.
Mol Cancer Ther
; 7(12): 3859-66, 2008 Dec.
Article
em En
| MEDLINE
| ID: mdl-19074858
ABSTRACT
Targeted delivery of IFNgamma to tumors has been achieved by fusing this cytokine with GCNGRC, a tumor neovasculature homing peptide. Although the therapeutic efficacy of this protein (called IFNgamma-NGR) in animal models is greater than that of IFNgamma, frequent administrations of IFNgamma-NGR may result in lower efficacy and tumor resistance. We investigated the role of indoleamine 2,3-dioxygenase (IDO), an IFNgamma-inducible enzyme that may down-regulate T cells by affecting local tryptophan catabolism in tumor resistance to repeated treatments with IFNgamma-NGR. The study was carried out in immunocompetent mice and in nu/nu mice bearing RMA lymphoma, B16F melanoma, or WEHI-164 fibrosarcoma and in vitro using cultured tumor cells. IDO activity was increased in lymphoma homogenates after multiple treatments with IFNgamma-NGR but not after a single treatment. Coadministration of 1-methyl-tryptophan, an inhibitor of IDO, increased tumor responses to multiple treatments in the lymphoma, melanoma, and fibrosarcoma models. No synergism between IFNgamma-NGR and 1-methyl-tryptophan was observed in vitro in tumor cell proliferation assays or in nu/nu tumor-bearing mice, suggesting that the antitumor effect was host mediated. We conclude that IDO is critically involved in tumor resistance to repeated treatments with IFNgamma-NGR, likely causing excessive stimulation of tryptophan catabolism and inhibiting antitumor immune mechanisms. Coadministration of IFNgamma-NGR with IDO inhibitors could represent a new strategy for increasing its antitumor activity.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Recombinantes de Fusão
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Regulação Neoplásica da Expressão Gênica
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Interferon gama
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Resistencia a Medicamentos Antineoplásicos
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Indolamina-Pirrol 2,3,-Dioxigenase
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Neoplasias
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Antineoplásicos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article