One specific molecular chemotherapy approach involves tumor cell transduction with the herpes simplex virus-thymidine kinase (HSV-tk) gene via a viral vector, followed by the systemic administration of the chemotherapy agent ganciclovir (GCV) (1). GCV is a prodrug that must be phosphorylated initially by the HSV-tk gene product to a monophosphate form and, subsequently, by the mammalian kinases to the cytotoxic triphosphate form. Once activated by this process, GCV functions as a purine analog that inhibits DNA polymerase thereby preventing DNA synthesis and inducing cell death (2,3). In addition, HSV-tk gene therapy mediates a "bystander effect," whereby nontransduced neighboring cells are also killed. This bystander effect appears to result from the transfer of active GCV metabolites through intercellular gap junctions between the transduced cells and the neighboring cells (4,5). Gene therapy with HSV- tk coadministered with GCV has been shown to be effective in various tumor models where it delayed local tumor growth and prolonged survival (7,8). Because radiation acts primarily by causing DNA strand breaks, HSV- tk gene therapy enhances radiation effects by interfering with DNA repair mechanisms. Other possible mechanisms may include an improved adenoviral-mediated gene transfer efficiency in irradiated cells (6), and radiation-induced cellular membrane damage may facilitate the transfer of cytotoxic nucleotide analogs from HSV-tk-expressing cells to neighboring nontransduced cells. Chhikara et al. (9) demonstrated that the combination therapy has a considerably better antimetastatic effect compared with HSV-tk gene therapy alone. They attributed this to the induction of a potent local and systemic immune response as evidenced by the abundance of CD4+ cells in the primary tumor. In a recent study Rosenberg et al. (10) showed that HSV-tk radiosensitized human glioma, U87 MG cells, after exposure to low concentrations of GCV. Importantly, this radiosensitization was most pronounced in the dose range that is used clinically (1-3 Gy). Preliminary results from an ongoing phase I/II trial evaluating the role of this combination for the treatment of prostate cancer indicate that this strategy is safe, but longer follow-up is required to demonstrate whether this therapy provides a therapeutic advantage compared with standard treatment (11).
Several chemotherapy agents have demonstrated activity for human cancer, including cisplatin, doxorubicin, methotrexate, vinblastine, and 5-fluorouracil (5-FU). However, the clinical utility and effectiveness of several of these drugs is generally limited by toxicity. Using the approach of gene therapy, a suicide gene encoding the bacterial and fungal enzyme cytosine deaminase (CD) can be transferred from bacteria and expressed in mammalian tumor cells. CD expressing cells can deaminate the relatively non-toxic prodrug 5-fluorocytosine (5-FC) to the highly toxic drug 5-FU. The effect of suicide gene therapy using an adenovirus vector expressing the CD gene combined with radiation therapy has been evaluated in several different tumor cell systems (12-14). The interaction between CD/5-FC gene therapy and radiation was compared when radiation preceded CD/5-FC treatment vs radiation followed by CD/5-FC treatment. Enhanced cell killing was seen only when the cells were exposed to the CD/5-FC before radiation making this finding significant for the future design of treatment strategies using the combination therapy. Adenovirus-mediated delivery of the CD gene used with 5-FC has also been used to achieve increased radiation killing of tumor cells in xenograft models. In a study using a colon cancer xenograft model, a significant growth delay was observed in the irradiated, Ad-CD infected tumors treated with 5-FC compared with radiation alone or the Ad-CD infected and 5-FC-treated tumors without radiation (15).
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