Transferrin lipoplex-mediated suicide gene therapy of oral squamous cell carcinoma in an immunocompetent murine model and mechanisms involved in the antitumoral response

Abstract

Suicide gene therapy has been used for the treatment of a variety of cancers. We reported previously the in vitro efficacy of the Herpes Simplex Virus Thymidine kinase (HSV-tk)/ganciclovir (GCV) system to mediate cytotoxicity in oral squamous cancer cells, using transferrin (Tf)-lipoplexes, prepared from cationic liposomes composed of 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP) and cholesterol. In the present study, we evaluated the antitumoral efficacy mediated by this lipoplex formulation in two suicide gene therapy strategies, HSV-tk/GCV and cytosine deaminase (CD)/5-fluorocytosine (5-FC), using a syngeneic, orthotopic murine model for head and neck squamous cell carcinoma. The cellular and molecular events associated with the antitumoral response elicited by both the therapeutic approaches were investigated by analyzing tumor cell death, tumor-infiltrating immune cells and tumor cytokine microenvironment. Significant tumor reduction was achieved upon intratumoral delivery of HSV-tk or CD genes mediated by Tf-lipoplexes, followed by intraperitoneal injection of GCV or 5-FC, respectively. Enhanced apoptosis, the recruitment of NK cells, CD4 and CD8 T-lymphocytes and an increase in the levels of several cytokines/chemokines were observed within the tumors. These observations suggest that suicide gene therapy with lipoplexes modifies the tumor microenvironment, and leads to the recruitment of immune effector cells that can act as adjuvants in reducing the tumor size.

Proteomic identification of salivary transferrin as a biomarker for early detection of oral cancer

“…Over-expression of the transferrin receptor (CD71), a type II transmembrane homodimer glycoprotein, has been reported in several cancers including lung [26,28,29], glioma [30], colon [30,31], pancreas [32] and breast [33]. Recently, human transferrin was demonstrated to enhance transfection efficiency of cationic liposome/DNA complexes into oral squamous carcinoma cells [34,35]. Taken together, these results and the findings from this study support salivary transferrin as a potential diagnostic marker for oral cancer.…”

Gene-Directed Enzyme Prodrug Cancer Therapy

“…Recently, a transferrin/lipoplex system containing 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP)/ cholesterol has been tested in vitro and in vivo [24]. The HSVTK gene was transferred to oral cancer cells in culture, using DOTAP/cholesterol polyplexes equipped with transferrin as a targeting moiety for dividing and nondividing cells.…”

The war against cancer: Suicide gene therapy

“…Iron-bound Tf is transported by TfR, which is over-expressed in tumor cells [62] . One of the therapeutic strategies of suicide cancer therapy is to decrease the level of iron [63] .…”