Doxorubicin Directs the Accumulation of Interleukin-12–Induced IFNγ into Tumors for Enhancing STAT1–Dependent Antitumor Effect

Abstract

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 IFNg into tumors and the signal transducer and activator of transcription 1 (Stat1)^dependent antitumor efficacy, the distribution of IFNg and the therapeutic end points, such asT-cell infiltration, inhibition of tumor vessel density, tumor growth inhibition, and inhibition of spontaneous tumor metastasis in wildtype 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-

Regulation of Interferon-Inducible Proteins by Doxorubicin via Interferon γ-Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling in Tumor Cells

“…Experimental studies have demonstrated that doxorubicin can augment immune responses that involve macrophage and NK cell activity (Ujhazy et al, 2003). It is noteworthy that antitumoral efficiency of some cytostatics, including doxorubicin, could be enhanced by coadministration of IFN␥ and an improved antitumor efficacy by coadministration of doxorubicin and IL-12 is dependent on the accumulation of IFN␥ in tumors (Wadler and Schwartz, 1990;Zhu et al, 2007). To date, detailed studies on the effects of doxorubicin on the pattern of tumor cell gene expression linked to immunomodulation or interferon signaling are not reported.…”

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

“…Tumor bearing were subject to control DNA (10 mg/mouse), control DNA plus doxorubicin (1 mg/kg), IL-12-encoding DNA (10 mg/ mouse), or IL-12-encoding DNA plus doxorubicin, and followed by electroporation as described previously. 50 Tumor volume was calculated by the formula:…”

Enhanced growth inhibition of metastatic lung tumors by intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes in mice

“…Co-administration of IL-12 protein or gene with traditional chemotherapeutic drugs, such as paclitaxel and doxorubicin, inhibits tumor growth and extends the survival time of tumor-bearing mice. 9,10 However, these traditional chemotherapeutic drugs also kill or stop normal cells dividing rapidly, resulting in marked systemic side effects, such as hematopoietic toxicity. 11,12 In contrast, differentiation agents have less serious side effects because of their effect on the process of carcinogenesis that tend to make cancer cells revert back to more normal differentiation.…”