From bench to bedside for gene-directed enzyme prodrug therapy of cancer

Abstract

Gene therapy of cancer offers the possibility of a targeted treatment that destroys tumors and metastases, but not normal tissues. In gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, the gene encoding an enzyme is delivered to tumor cells, followed by administration of a prodrug, which is converted locally to a cytotoxin by the enzyme. The producer cells as well as surrounding bystanders are subsequently killed. Promising results have meant that suicide gene therapy has reached multicenter phase III clinical trials. This review will discuss the development, efficiency, mode of action and pharmacokinetics of seven GDEPT systems in vitro and in vivo. We will review the latest data of those systems in clinical trials (herpes simplex virus thymidine kinase/gancyclovir, bacterial cytosine deaminase/5-fluorocytosine, bacterial nitroreductase/CB1954 and cytochrome P450/cyclophosphamide), as well as the development of more recent and experimental systems which are not yet in clinical trials (P450 reductase/tirapazamine, carboxypeptidase/CMDA, horseradish peroxidase/indole-3-acetic acid or paracetamol and others).

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

“…Tumor sizes (length L and width W) were measured twice a week using an electronic digital caliper (VWR international, Marlboro, MA). A second CPA treatment cycle was administered when the tumors reached a size of B800 mm 3 , that is, day 35 after the first CPA treatment. Tumor volumes were calculated using the formula: volume ¼ p/6 (L Â W) 3/2 .…”

“…Intratumoral prodrug activation may be enhanced by introduction of prodrugactivation enzymes of bacterial, viral or mammalian origin using a variety of gene therapy vectors, including retroviruses, adenoviruses, herpes viruses, as well as nonviral vectors. [1][2][3] Chemosensitization is achieved when an anticancer prodrug is activated locally in tumor cells, which augments cytotoxic responses, both in the prodrugactivating tumor cell and in naive bystander tumor cells exposed to diffusible cytotoxic metabolites.…”

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

“…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.…”

In vivo characterization of horseradish peroxidase with indole-3-acetic acid and 5-bromoindole-3-acetic acid for gene therapy of cancer

“…1,2 To this end, the horseradish peroxidase (HRP) has been used to convert the indole prodrug indole-3-acetic acid (IAA), and several of its analogs, to toxic agents to induce cell kill in vitro. [3][4][5] IAA is a plant auxin involved in the regulation of plant cellular growth, division, and differentiation, as well as a natural metabolite in mammals of the amino-acid tryptophan by monoamine oxidase.…”