Strategies Using Nonviral Vectors In Cancer Gene Therapy

Various nonviral vector systems have been used to deliver DNA into cancer cells to induce an antitumor effect. Naked DNA encoding genes ranging from cytokine genes to tumor antigen genes have been delivered alone (63), by gene gun (64,65), or by electroporation (66,67), resulting in significantly induced cytokine levels or specific antigen expression. Electroporation has also been used to introduce plasmids that encode antisense RNA against E6 and E7 mRNA to human papilloma virus (HPV) expressing cancer cells, which resulted in a significant inhibition of tumor growth (68). Another approach involved gene gun-mediated delivery of heat-shock protein 70 (Hsp70) linked to the HPV16 E7 tumor antigen gene into antigen presenting cells (APCs). It led to an enhanced E7-specific immune response of lymphocytes after exposure to these transfected APCs (69).

Lipoplex has been shown to greatly enhance the efficiency of gene transfer in the spinal cord (70), lungs (71), and tumors (72), both, by intratumoral injection and intravenous injection. That delivery of cationic liposomes is safe in humans, even with the high charge ratio of cationic liposome to DNA, was shown early in gene therapy trials (41,73). This was in contrast to the previous understanding that the positive charge of cationic liposomes led to potential harmfull aggregations with serum proteins that could impede blood circulation and hemostasis. In clinical studies, complex of DNA and cationic liposomes induces gene expression resulting in reduction of tumor size (74). That repeated administration of lipoplex is feasible and well supported was made evident in a recent clinical study in patients with cystic fibrosis (75). In that study, repeated administration of the cystic fibrosis transmembrane regulator (CFTR) cDNA in DC-Chol/DOPE cationic liposomes resulted in continued expression of CFTR in the airway epithelium.

LPD also plays an increasingly important role in antitumor gene therapy. An interesting method is to deliver a plasmid containing an unmethylated CpG motif flanked by two 5'-purines and two 3'-pyrimidines in the form of LPD. This approach induced proin-flammatory cytokine levels leading to a nonspecific immune response and it showed a remarkable decrease of tumor burden in lung cancers (76). In order to enhance a specific immune response against tumor antigens, such as a peptide epitope of the HPV16 E7 protein expressed by cervix cancer cells, entrapping of the epitope peptide in LPDs was tested. With this approach, specific immunity was induced and complete tumor regression was observed in all tumor-bearing mice treated with LPD/E7 nanoparticles (63).

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