PURPOSE: To examine the mechanism by which doxorubicin plus interleukin-12 (IL-12) gene transfer induces enhanced therapeutic efficacy against tumors. EXPERIMENTAL DESIGN: Tumor-bearing mice were treated with doxorubicin, IL-12-encoding plasmid DNA, doxorubicin plus IL-12-encoding plasmid DNA, or plasmid DNA control. Doxorubicin was systemically given via i.p. injection, and IL-12 was systemically expressed via i.m. injection. To show that doxorubicin enhances the accumulation of IL-12-induced IFN gamma into tumors and the signal transducer and activator of transcription 1 (Stat1)-dependent antitumor efficacy, the distribution of IFN gamma and the therapeutic end points, such as T-cell infiltration, inhibition of tumor vessel density, tumor growth inhibition, and inhibition of spontaneous tumor metastasis in wild-type and Stat1(-/-) host and tumors were determined after the treatment at the indicated time points. RESULTS: In this study, a novel mechanism was unveiled. We discovered that doxorubicin enhances the accumulation of IL-12-induced IFN gamma in tumors. The doxorubicin-mediated accumulation of IFN gamma in tumors is caused by an increased accumulation of IFN gamma-secreting immune cells and not by a direct translocation of IFN gamma protein into tumors. Depletion of immune cells reverses the doxorubicin-mediated accumulation of IFN gamma into tumors and reverses the inhibition of tumor vessel density induced by coadministration of doxorubicin and IL-12 DNA. Knocking out IFN gamma signaling in the tumor host reverses the significant inhibition of tumor growth by coadministration of doxorubicin and IL-12. CONCLUSIONS: The enhanced antitumor efficacy by coadministration of doxorubicin and IL-12 is dependent on the accumulation of IFN gamma in tumors. This discovery provides a possible strategy to reduce side effects caused by IL-12.
PURPOSE: To examine the mechanism by which doxorubicin plus interleukin-12 (IL-12) gene transfer induces enhanced therapeutic efficacy against tumors. EXPERIMENTAL DESIGN:Tumor-bearing mice were treated with doxorubicin, IL-12-encoding plasmid DNA, doxorubicin plus IL-12-encoding plasmid DNA, or plasmid DNA control. Doxorubicin was systemically given via i.p. injection, and IL-12 was systemically expressed via i.m. injection. To show that doxorubicin enhances the accumulation of IL-12-induced IFN gamma into tumors and the signal transducer and activator of transcription 1 (Stat1)-dependent antitumor efficacy, the distribution of IFN gamma and the therapeutic end points, such as T-cell infiltration, inhibition of tumor vessel density, tumor growth inhibition, and inhibition of spontaneous tumor metastasis in wild-type and Stat1(-/-) host and tumors were determined after the treatment at the indicated time points. RESULTS: In this study, a novel mechanism was unveiled. We discovered that doxorubicin enhances the accumulation of IL-12-induced IFN gamma in tumors. The doxorubicin-mediated accumulation of IFN gamma in tumors is caused by an increased accumulation of IFN gamma-secreting immune cells and not by a direct translocation of IFN gamma protein into tumors. Depletion of immune cells reverses the doxorubicin-mediated accumulation of IFN gamma into tumors and reverses the inhibition of tumor vessel density induced by coadministration of doxorubicin and IL-12 DNA. Knocking out IFN gamma signaling in the tumor host reverses the significant inhibition of tumor growth by coadministration of doxorubicin and IL-12. CONCLUSIONS: The enhanced antitumor efficacy by coadministration of doxorubicin and IL-12 is dependent on the accumulation of IFN gamma in tumors. This discovery provides a possible strategy to reduce side effects caused by IL-12.
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Authors: Ioannis Alagkiozidis; Andrea Facciabene; Carmine Carpenito; Fabian Benencia; Zdenka Jonak; Sarah Adams; Richard G Carroll; Phyllis A Gimotty; Rachel Hammond; Gwen-äel Danet-Desnoyers; Carl H June; Daniel J Powell; George Coukos Journal: J Transl Med Date: 2009-12-10 Impact factor: 5.531
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