Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha.
OBJECTIVE
Subnanogram doses of NGR-tumor necrosis factor (TNF), a TNF-alpha 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.


METHODS
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.
Sacchi
Angelina
A
DIBIT-Department of Oncology, Cancer Immunotherapy and Gene Therapy Program, San Raffaele H. Scientific Institute, Milan, Italy.
Gasparri
Anna
A
Gallo-Stampino
Corrado
C
Toma
Salvatore
S
Curnis
Flavio
F
Corti
Angelo
A
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy; D002945:Cisplatin / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D000093542:Gemcitabine
D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine