TY - JOUR
T1 - Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-α
AU - Sacchi, Angelina
AU - Gasparri, Anna
AU - Gallo-Stampino, Corrado
AU - Toma, Salvatore
AU - Curnis, Flavio
AU - Corti, Angelo
PY - 2006/1/1
Y1 - 2006/1/1
N2 - Purpose: Subnanogram doses of NGR-tumor necrosis factor (TNF), a TNF-α derivative able to target tumor neovessels, can enhance the antitumor activity of doxorubicin and melphalan in murine models. We have examined the antitumor activity of NGR-TNF in combination with various chemotherapeutic drugs acting via different mechanisms, including, besides doxorubicin and melphalan, cisplatin, paclitaxel, and gemcitabine. Experimental Design: Chemotherapeutic drugs were tested alone and in combination with NGR-TNF (0.1 ng) in murine lymphoma, fibrosarcoma, and mammary adenocarcinoma models. Different administration schedules have been tested and the effects on tumor growth, animal weight, tumor perfusion, and cell cytotoxicity have been investigated. Results: Pretreatment with NGR-TNF enhanced the response to all these drugs although to a different extent. The increased efficacy was not accompanied by increased toxicity at least as judged from the loss of animal weight. The synergistic effect was transient, maximal synergism being observed with a 2-hour delay between NGR-TNF and drug administrations in all models and with all drugs tested. NGR-TNF did not increase the in vitro cytotoxicity of chemotherapeutic drugs against tumor cells, suggesting that the in vivo synergism depends on NGR-TNF effects on host cells rather than on tumor cells. Conclusions: Targeted delivery of low doses of NGR-TNF to the tumor vasculature can increase the efficacy of various drugs acting via different mechanisms. Optimal administration schedule requires 2 hours of pretreatment with NGR-TNF independently from the mechanism of drug cytotoxicity. This work could provide important information for designing clinical studies with NGR-TNF in combination with chemotherapeutic drugs.
AB - Purpose: Subnanogram doses of NGR-tumor necrosis factor (TNF), a TNF-α derivative able to target tumor neovessels, can enhance the antitumor activity of doxorubicin and melphalan in murine models. We have examined the antitumor activity of NGR-TNF in combination with various chemotherapeutic drugs acting via different mechanisms, including, besides doxorubicin and melphalan, cisplatin, paclitaxel, and gemcitabine. Experimental Design: Chemotherapeutic drugs were tested alone and in combination with NGR-TNF (0.1 ng) in murine lymphoma, fibrosarcoma, and mammary adenocarcinoma models. Different administration schedules have been tested and the effects on tumor growth, animal weight, tumor perfusion, and cell cytotoxicity have been investigated. Results: Pretreatment with NGR-TNF enhanced the response to all these drugs although to a different extent. The increased efficacy was not accompanied by increased toxicity at least as judged from the loss of animal weight. The synergistic effect was transient, maximal synergism being observed with a 2-hour delay between NGR-TNF and drug administrations in all models and with all drugs tested. NGR-TNF did not increase the in vitro cytotoxicity of chemotherapeutic drugs against tumor cells, suggesting that the in vivo synergism depends on NGR-TNF effects on host cells rather than on tumor cells. Conclusions: Targeted delivery of low doses of NGR-TNF to the tumor vasculature can increase the efficacy of various drugs acting via different mechanisms. Optimal administration schedule requires 2 hours of pretreatment with NGR-TNF independently from the mechanism of drug cytotoxicity. This work could provide important information for designing clinical studies with NGR-TNF in combination with chemotherapeutic drugs.
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U2 - 10.1158/1078-0432.CCR-05-1147
DO - 10.1158/1078-0432.CCR-05-1147
M3 - Article
C2 - 16397040
AN - SCOPUS:31544436380
VL - 12
SP - 175
EP - 182
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 1
ER -