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.

Influence of Autologous and Homologous Blood Transfusion on Interleukins and Tumor Necrosis Factor-α in Peri-operative Patients with Esophageal Cancer

“…Meanwhile, it also participates in pathological processes such as endotoxin shock. Additionally, TNF-α also has multiple functions of anti-inflammation and killing tumor cells due to its synergistic action with other bioactive factors (Chen et al, 2010;Fujiwara et al, 2013;Su et al, 2013). Previous research discovered that TNF-α could kill the residual tumors through inducing cell apoptosis, and many anti-tumor agents (cisplatin, etc.)…”

Light-Triggerable Liposomes for Enhanced Endolysosomal Escape and Gene Silencing in PC12 Cells

“…Among these nanomaterials, liposomes, especially including cationic lipid components, have attracted significant interests as a drug and/or gene delivery vehicle since the 1980s 8, 9, 10. Up-to-date, various types of liposomes have been clinically used to improve the efficacy and biodistribution of drugs, including cancer therapeutics 11, 12. In recent years, a number of studies reported the application of liposomal carriers to various gene-targeting strategies in cancer gene therapy 3, 13, 14, 15, 16.…”

Mesenchymal Stem Cell–Mediated, Tumor Stroma–Targeted Radioiodine Therapy of Metastatic Colon Cancer Using the Sodium Iodide Symporter as Theranostic Gene

“…An array of therapy proteins has already been demonstrated to be successfully delivered to tumor environments using eMSC, including interferon-g, TNF-related apoptosis-inducing ligands, IL-12, the chemokine CX3CL1, and various suicide genes (4,5,24,25). Recent studies have shown that adoptively applied MSCs can also efficiently home to tumor metastases, opening the door to the potential use of eMSC for treatment of metastatic disease (26)(27)(28)(29).…”