Suicide Gene Therapy against Cancer

Abstract

A major limitation of conventional chemotherapies used in cancer treatments today are low therapeutic indices and side effects that result from drug effects on normal tissues (off target). One of the most innovative approaches to developing antineoplastic agents with increased tumor selectivity is the use of suicide gene therapy. Suicide gene therapy involves delivering a gene product in proximity to the targeted cancer tissue through various targeted delivery methods followed by tissue/tumor-specific expression of the gene product which then converts a systemically available pro-drug into an active drug within the tumor locale. Here we summarize the concept of gene therapy for cancer and introduce the most frequently used suicide gene therapy systems. In addition we discuss viral, molecular and cellular vectors and their advantages and disadvantages. Finally, we describe the clinical applications, limitations and potential side effects of suicide gene therapy to date.

Mesenchymal stem cells: A new platform for targeting suicide genes in cancer

“…The term of gene directed enzyme prodrug therapy (GDEPT) is one of the promising alternatives to conventional chemotherapy because it minimizes the systemic toxicities of conventional chemotherapy drugs and refer to expression of a suicide gene in tumor cells for the in situ conversion of a pro‐drug into cytotoxic metabolites (Greco & Dachs, ; Springer & Niculescu‐Duvaz, ). The first attempt to use of suicide genes against cancer was in 1986 by Moolten et al (Rajab et al, ). These points must consider in selection of suicide genes; Intended gene must encodes an enzyme that did not exist in normal cells or there is no enzyme with similar function in cells; Minimal toxicity of prodrug before activation in body and maximum toxicity after converting to active drug in tumor location; high kinetic enzyme activity or high affinity to target prodrug and finally active drug must diffuse in whole tumor mass by Bystander effects (Both, ; Rajab et al, ; Zarogoulidis et al, ).…”

“…The first attempt to use of suicide genes against cancer was in 1986 by Moolten et al (Rajab et al, ). These points must consider in selection of suicide genes; Intended gene must encodes an enzyme that did not exist in normal cells or there is no enzyme with similar function in cells; Minimal toxicity of prodrug before activation in body and maximum toxicity after converting to active drug in tumor location; high kinetic enzyme activity or high affinity to target prodrug and finally active drug must diffuse in whole tumor mass by Bystander effects (Both, ; Rajab et al, ; Zarogoulidis et al, ). This mentions to the demolition of tumor cells that are not directly expressing the suicide gene.…”

“…The term of gene directed enzyme prodrug therapy (GDEPT) is one of the promising alternatives to conventional chemotherapy because it minimizes the systemic toxicities of conventional chemotherapy drugs and refer to expression of a suicide gene in tumor cells for the in situ conversion of a pro-drug into cytotoxic metabolites (Greco & Dachs, 2001;Springer & Niculescu-Duvaz, 2000). The first attempt to use of suicide genes against cancer was in 1986 by Moolten et al (Rajab et al, 2013). These points must consider in selection of suicide genes;…”

“…Achieving the specified purpose requires vehicles that encapsulate the gene and deliver it particularly to cancer cell and cancer local environment of the tumor. In gene therapy and especially cancer gene therapy, at first we need to utilize vehicle so called vector that includes a set of criteria; having tumor tropism (specificity for tumor microenvironments), do not able to elicit an immune response and safety (Hacein-Bey-Abina et al, 2002;Rajab, Nelson, Keung, & Conrad, 2013). From the first reports of gene therapy in 1960-1970 to present, there are three types of gene delivery systems into the target cell (Collins & Thrasher, 2015).…”

“…Retrovirus, lentivirus, and adenovirus are common viral vectors. In the field of gene therapy with viral vectors there are two major obstacles in terms of the safety and toxicity of these vectors that limit the clinical potential of this approach (i.e., insertional mutagenesis of retroviral vectors and intensive immune reaction of adenoviral vectors) (Collins et al, 2008;Nayerossadat, Maedeh, & Ali, 2012;Rajab et al, 2013;Waehler, Russell, & Curiel, 2007). Molecular vectors including, naked DNA and application of cationic polymers such as polyethylenimine or poly-L-lysine, cationic peptides, and cationic liposomes.…”