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

Authors' Affiliation: Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana

Requests for reprints: Shulin Li, Department of Comparative Biomedical Sciences, Louisiana State University, Skip Bertman Drive, Baton Rouge, LA 70803. Phone: 225-578-9032; Fax: 225-578-9895; E-mail: sli{at}vetmed.lsu.edu.

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 into tumors and the signal transducer and activator of transcription 1 (Stat1)–dependent antitumor efficacy, the distribution of IFN 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 in tumors. The doxorubicin-mediated accumulation of IFN in tumors is caused by an increased accumulation of IFN-secreting immune cells and not by a direct translocation of IFN protein into tumors. Depletion of immune cells reverses the doxorubicin-mediated accumulation of IFN into tumors and reverses the inhibition of tumor vessel density induced by coadministration of doxorubicin and IL-12 DNA. Knocking out IFN 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 in tumors. This discovery provides a possible strategy to reduce side effects caused by IL-12.