title: Systemic TNFα gene therapy synergizes with liposomal doxorubicine in the treatment of metastatic cancer.
abstract: Tumor necrosis factor alpha (TNFα) is a potent antitumoral cytokine, either killing tumor cells directly or affecting the tumor vasculature leading to enhanced accumulation of macromolecular drugs. Due to dose limiting side effects systemic administration of TNFα protein at therapeutically active doses is precluded. With gene vectors, tumor restricted TNFα expression can be achieved and in principle synergize with chemotherapy. Synthetic gene carriers based on polyamines were intravenously injected, which either passively accumulate within the tumor or specifically target the epidermal growth factor receptor. A single intravenous injection of TNFα gene vector promoted accumulation of liposomal doxorubicine (Doxil) in murine neuroblastoma and human hepatoma by enhancing tumor endothelium permeability. The expression of transgenic TNFα was restricted to tumor tissue. Three treatment cycles with TNFα gene vectors and Doxil significantly delayed tumor growth in subcutaneous murine Neuro2A neuroblastoma. Also tumors re-growing after initial treatment were successfully treated in a fourth cycle pointing at the absence of resistance mechanisms. Systemic Neuro2A metastases or human LS174T colon carcinoma metastases in liver were also successfully treated with this combined approach. In conclusion, this schedule opens the possibility for the efficient treatment of tumors metastases otherwise not accessible for macromolecular drug carriers.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biotechnology, Center for System based Drug Research, Ludwig Maximilians University, Munich, Germany.
authors.forename: Baowei
authors.initials: B
authors.lastname: Su
authors.forename: Arzu
authors.initials: A
authors.lastname: Cengizeroglu
authors.forename: Katarina
authors.initials: K
authors.lastname: Farkasova
authors.forename: Joana R
authors.initials: JR
authors.lastname: Viola
authors.forename: Martina
authors.initials: M
authors.lastname: Anton
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Ellwart
authors.forename: Rudolf
authors.initials: R
authors.lastname: Haase
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001681:Biological Assay; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009362:Neoplasm Metastasis / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D014162:Transfection / Q000379:methods; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin