Crucial role for interferon gamma in the synergism between tumor vasculature-targeted tumor necrosis factor alpha (NGR-TNF) and doxorubicin.
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.
Department of Biological and Technological Research and Cancer Immunotherapy and Gene Therapy Program, San Raffaele H Scientific Institute, Milan, Italy.
Angelina
A
Sacchi
Anna
A
Gasparri
Flavio
F
Curnis
Matteo
M
Bellone
Angelo
A
Corti
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D007371:Interferon-gamma / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D014409:Tumor Necrosis Factor-alpha; C464840:tumor Necrosis Factor-alpha, CNGRC fusion protein, mouse; D004317:Doxorubicin; D007371:Interferon-gamma