Frontiers in Suicide Gene Therapy of Cancer

Abstract

The National Cancer Institute (NCI) and the American Cancer Society (ACS) predict that 1,638,910 men and women will be diagnosed with cancer in the USA in 2012. Nearly 577,190 patients will die of cancer of all sites this year. Patients undergoing current systemic therapies will suffer multiple side effects from nausea to infertility. Potential parents, when diagnosed with cancer, will have to deposit oocytes and sperms prior to starting systemic radiation or chemo-therapy for the future genetic testing and in vitro fertilization, while trying to avoid risks of iatrogenic mutations in their germ cells. Otherwise, children of parents treated with systemic therapies, will be at high risk of developing genetic disorders. According to these predictions, this year will carry another, very poor therapeutic record again.The ultimate goal of cancer therapy is the complete elimination of all cancer cells, while leaving all healthy cells unharmed. One of the most promising therapeutic strategies in this regard is cancer suicide gene therapy (CSGT), which is rapidly progressing into new frontiers.The therapeutic success, in CSGT, is primarily contingent upon precision in delivery of the therapeutic transgenes to the cancer cells only. This is addressed by discovering and targeting unique or / and over-expressed biomarkers displayed on the cancer cells and cancer stem cells. Specificity of cancer therapeutic effects is further enhanced by designing the DNA constructs, which put the therapeutic genes under the control of the cancer cell specific promoters. The delivery of the suicidal genes to the cancer cells involves viral, as well as synthetic vectors, which are guided by cancer specific antibodies and ligands. The delivery options also include engineered stem cells with tropisms towards cancers. Main mechanisms inducing the cancer cells' deaths include: transgenic expression of thymidine kinases, cytosine deaminases, intracellular antibodies, telomeraseses, caspases, DNases. Precautions are undertaken to eliminate the risks associated with transgenesis.Progress in genomics and proteomics should help us in identifying the cancer specific biomarkers and metabolic pathways for developing new strategies towards clinical trials of targeted and personalized gene therapy of cancer.

The war against cancer: Suicide gene therapy

“…The most studied systems are herpes simplex virus thymidine kinase gene (HSV-TK) with prodrug ganciclovir (GCV), cytosine deaminase gene (CD), carboxyl esterase/irinotecan (CE/CPT-11), varicella zoster virus thymidine kinase/6-methoxypurine arabinonucleoside (Vzvtk/araM), nitroreductase Nfsb/5-(aziridin -1-yl)-2, 4-dinitrobenzamide (NTR/CB1954), carboxypeptidase G2/4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-L-glutamic acid (CPG2/CMDA), cytochrome p450-ifosfamide, and cytochrome p450-cyclophosphamide [6] . Additionally, there are other systems that are not widely used such as the purine nucleoside phosphorylase (PNP), linamarase, β-galactosidase, and nitroreductase [7] .…”

“…The VZV-TK suicide gene system has generally poor efficacy on the activated prodrug against some cancer cell types. However, it has been recently developed as improved potency anti-herpetic pyrimidine nucleoside analogues, including the novel prodrug (E)-5-(2-bromo vinyl)-2-deoxyuridine (BVDU) which is 80-fold more toxic to cells [6] . Cytosine deaminase/5-FC system (CD/5-FC).…”

Suicide Gene Therapy against Cancer

“…For example, the first successful gene therapy trial, which corrected x-linked severe combined immunodeficiency by inserting the gene for the common gamma chain into hematopoietic Citation [34]. An important advantage of these vectors is that they are considered to be safer than viral vectors because of the reduced chance for insertional mutagenesis or side effects from immune reactions to the vector [35].…”

Trypsin-antitrypsin Imbalance in Immune Escape and Clonal Proliferation of Pancreatic Cancer

“…In addition, AAT also can regulate immune response, affect the removal of antigen-antibody immune complex, and activate the complement and inflammatory response [25][26][27][28][29]. AAT can be synthesized by mononuclear cells, alveolar macrophages and epithelial cells and those synthesized by extrahepatic cells play an important role in the regulation of local tissue injury.…”