In vivo growth inhibitory effect of iterative wild-type p53 gene transfer in human head and neck carcinoma xenografts using glucosylated polyethylenimine nonviral vector

Abstract

Polyethylenimine ( PEI ) derivatives are polycationic nonviral vectors for gene transfer. Previous results achieved in vitro in head and neck cancer cells demonstrated that glucosylated PEI yields higher gene transfer efficiency and longer transgene expression than unsubstituted PEI. Using glucosylated PEI, p53 gene transfer was successfully achieved with subsequent recovery of P53 protein expression and induction of spontaneous apoptosis. The present study reports in vivo data achieved in human head and neck squamous cell carcinoma xenografted mice. Using biotinylated PEI and histochemistry analysis, the vector was found to diffuse in the proliferating cells of the tumor tissue, sparing necrotic areas. No diffusion was observed inside keratinized area composed of nonproliferating, mature differentiated cells. Using green fluorescent protein ( GFP ) transfection and fluorescence microscopy, the transgene expression was mainly observed at the periphery of the tumor containing proliferating cells. GFP expression appeared lower inside the tumor depth. Quantitative transgene expression kinetics was then determined using luciferase as reporter gene. The maximal transgene expression was achieved 48 hours after intratumoral injection of glucosylated PEI / DNA complexes. The highest gene transfer efficacy was achieved 48 hours after two intratumoral injection. After transfection of wild -type p53, tumor growth inhibition was observed in tumor -bearing mice receiving intratumoral injection of glucosylated PEI / DNA complexes repeated twice weekly. Tumor growth inhibition was maintained under continuous treatment using the same schedule. In all experiments, no noticeable toxicity was observed. The present results demonstrate the feasibility and the tumor growth inhibition potency of nonviral gene transfer using glucosylated polyethylenimine.

Loss of p53 Expression Correlates with Metastatic Phenotype and Transcriptional Profile in a New Mouse Model of Head and Neck Cancer

“…p53 has been evaluated as a predictive marker for lymph node metastasis and response to ionizing radiation and chemotherapy (28)(29)(30). Reintroduction of wildtype p53 into HNSCC lines and xenografts results in growth inhibition and sensitization to chemotherapy drugs (31,32). Patients with Li-Fraumeni syndrome have decreased p53 function and higher risk of multiple cancers, including those of the head and neck (33).…”

Efficacy and cytotoxicity of cationic‐agent–mediated nonviral gene transfer into osteoblasts

“…20 Biodegradable cationic gelatin was introduced as a low toxic and manipulable gene transfer agent for liver, 21 mucosa, 22 and muscle 23 cells. An artificial, cationic polymer, polyetheylenimine (PEI), has been demonstrated to be effective for in vitro and in vivo gene transfer, including liver, 24 brain, 25 and cancer 26 cells. These cationic agents increase gene transfer efficacy consistently compared with naked DNA.…”

Intraperitoneal linear polyethylenimine (L-PEI)-mediated gene delivery to ovarian carcinoma nodes in mice

“…Among them, polyethylenimine (PEI) is considered as the most effective. Preclinical data are available for hepatocellular carcinoma, 1 pancreatic tumors, 2,3 ovarian carcinoma, 4,5 head-andneck cancer 6,7 and lung cancer. [8][9][10] More importantly, the first clinical data were published recently, which show dramatic bladder tumor remission in two patients.…”