Doxorubicin directs the accumulation of interleukin-12 induced IFN gamma into tumors for enhancing STAT1 dependent antitumor effect.
OBJECTIVE
To examine the mechanism by which doxorubicin plus interleukin-12 (IL-12) gene transfer induces enhanced therapeutic efficacy against tumors.


METHODS
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.
Zhu
Shiguo
S
Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Waguespack
Marian
M
Barker
Steven A
SA
Li
Shulin
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D050794:STAT1 Transcription Factor / Q000235:genetics*
D000970:Antineoplastic Agents; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D018664:Interleukin-12; D004317:Doxorubicin; D007371:Interferon-gamma