Combination therapy with AG-490 and interleukin 12 achieves greater antitumor effects than either agent alone.
Mol Cancer Ther
; 1(11): 893-9, 2002 Sep.
Article
en En
| MEDLINE
| ID: mdl-12481410
ABSTRACT
Constitutive activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) occurs at very high frequency in various hematopoietic malignancies and solid tumors. It has been demonstrated that the tyrosine kinase inhibitor, AG-490, selectively blocks JAK activity and completely eliminates leukemia cells in a severe combined immunodeficient (SCID) mouse model. Because many cytokines, including interleukin (IL)-12, have been shown to signal through JAK/STAT pathways, AG-490 may inhibit cytokine-based cancer therapy. In this study, we evaluated the effects of AG-490 on IL-12 functional signaling and IL-12-mediated antitumor response in vivo. Previous studies have established the critical roles of macrophages and IFN-gamma in mediating IL-12-induced antitumor effects. Our results show that in vivo administration of AG-490 causes tumor cell apoptosis but does not inhibit IL-12-mediated macrophage activation and IFN-gamma production by lymphocytes. Furthermore, our data indicate that combined therapy with AG-490 and IL-12-induces greater antitumor effects than either agent alone in a murine myeloma tumor model. These results suggest that JAK/STAT inhibitors deserve further investigation for use with IL-12 therapy in treating human cancers with elevated JAK/STAT activity.
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Banco de datos:
MEDLINE
Asunto principal:
Protocolos de Quimioterapia Combinada Antineoplásica
/
Interleucina-12
/
Tirfostinos
/
Neoplasias
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Mol Cancer Ther
Asunto de la revista:
ANTINEOPLASICOS
Año:
2002
Tipo del documento:
Article
País de afiliación:
Estados Unidos