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[Cancer Research 64, 7150-7155, October 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Crucial Role for Interferon {gamma} in the Synergism between Tumor Vasculature-Targeted Tumor Necrosis Factor {alpha} (NGR-TNF) and Doxorubicin

Angelina Sacchi1, Anna Gasparri1, Flavio Curnis1, Matteo Bellone1 and Angelo Corti1

1 Department of Biological and Technological Research and Cancer Immunotherapy and Gene Therapy Program, San Raffaele H Scientific Institute, Milan, Italy

NGR-TNF is a derivative of TNF-{alpha}, consisting of TNF fused to CNGRCG, a tumor vasculature-targeting peptide. Previous studies showed that NGR-TNF can exert synergistic antitumor effects with doxorubicin and with other chemotherapeutic drugs in murine models. In this study, we have investigated the role of endogenous IFN-{gamma} on the antitumor activity of NGR-TNF in combination with doxorubicin. The study was carried out using murine B16F1 melanoma and TS/A mammary adenocarcinoma implanted subcutaneously in (a) immunocompetent mice, (b) athymic nude mice, and (c) IFN-{gamma}–knockout mice. Synergism between NGR-TNF and doxorubicin was observed in immunocompetent mice but not in nude or IFN-{gamma}–knockout mice. Preadministration of a neutralizing anti-IFN-{gamma} antibody to immunocompetent mice inhibited the NGR-TNF/doxorubicin synergism, whereas administration of IFN-{gamma} to nude and to IFN-{gamma}–knockout mice restored the synergistic activity. The synergism in nude mice was restored also by transfecting tumor cells with the IFN-{gamma} cDNA. Administration of NGR-TNF in combination with IFN-{gamma} to nude mice, but not of NGR-TNF alone, doubled the penetration of doxorubicin in TS/A tumors. These findings point to a crucial role for locally produced IFN-{gamma} in tumor vascular targeting with NGR-TNF and doxorubicin. Finally, addition of IFN-{gamma} to the treatment of immunocompetent mice with NGR-TNF/doxorubicin induced only modest improvement in response, suggesting that exogenous IFN-{gamma} can improve the therapeutic activity of these drugs only in case of suboptimal production of endogenous IFN-{gamma}.




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