Suicide genes for cancer therapy

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

“…One way to circumvent these restrictions and to further utilize OV combinations is to incorporate a suicide gene strategy that allows specific gene transduction of tumor cells with nonmammalian enzymes that convert innocuous prodrugs into highly toxic chemotherapeutic compounds within the tumor. 13 VSV represents an excellent choice as a vector for suicide gene transduction because of selective cancer cell tropism and the relative ease of foreign gene insertion. 4,5,14 VSV engineered to express suicide enzymes allow the conversion of non-toxic prodrug into a toxic form only at the site of viral replication, thus generating specific bystander killing at the tumor site.…”

“…Recombinant VSV carrying the Herpes virus TK enzyme has been shown to phosphorylate the non-toxic prodrug ganciclovir, facilitating its DNA integration and subsequent local toxicity. 13,15 A similar strategy was employed with VSV expressing the human sodium iodine symporter that resulted in the accumulation of radioactive iodine at the tumor site. 16 Both of these recombinant VSV strategies were shown to delay tumor growth in murine models; however, their action is restricted to cells that are directly infected by VSV.…”

“…The high solubility of 5FU promotes a strong bystander effect on neighboring tumor cells that are not actively infected, which confers an important advantage to this combination compared with other suicide gene strategies. 13,17 The CD::UPRT-5FC system is thus a powerful tool for cancer therapy, including oncolytic experimental strategies. [18][19][20][21][22] In addition to these suicide gene approaches, VSV variants that possess increased oncolytic potential compared with wild-type VSV have been characterized.…”

Genetically modified macrophages expressing hypoxia regulated cytochrome P450 and P450 reductase for the treatment of cancer

“…The 4-hydroxy intermediate metabolites are freely diffusible among tumour cells, thus enabling a relatively small number of P450-expressing cells to kill more of the surrounding non-P450 expressing cells via a mechanism known as the bystander effect. Direct delivery of the cytochrome P450 gene into tumour cells followed by CPA treatment significantly inhibits tumour growth and this local activation of CPA in the tumour cells requires a lower therapeutic dose of the prodrug, thereby reducing the systemic toxicity caused by CPA conversion in the liver (11,12). P450 reductase (P450R) catalyzes the electron transfer required for the P450 enzyme activity and this flavoenzyme is ubiquitously expressed in all cells including malignant cells (13).…”

“…P450 reductase (P450R) catalyzes the electron transfer required for the P450 enzyme activity and this flavoenzyme is ubiquitously expressed in all cells including malignant cells (13). However, the wide variation in the endogenous expression levels of this enzyme means that it may be rate- (11,12,14,15). Thus, overexpression of P450R can significantly increase the potency of a P450/CPA based GDEPT strategy.…”