Molecular Chemotherapy With rAAV

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Delivery of a gene-encoded toxin into cancer cells to achieve tumor eradication is usually performed by indirect killing through activation by a prodrug. This approach has focused mainly on delivery of the herpes simplex virus thymidine kinase (HSV-tk) gene. Expression of HSV- tk results in replicating tumor cells having enhanced sensitivity to nucleoside analogs, such as ganciclovir (GCV) or acyclovir. GCV is phosphory-lated initially by TK and subsequently by cellular factors to a triphosphate form that becomes incorporated into cellular DNA (81). This inhibits both DNA synthesis and RNA polymerase activity resulting in cell death (81).

Although a majority of both preclinical and clinical gene therapy studies using molecular chemotherapy approaches have been conducted with recombinant adenoviral vectors, AAV-mediated in vivo studies have also indicated therapeutic benefits for tumor regression. Selective killing of a fetoprotein (AFP)-positive hepatocellular carcinoma cells by AAV-mediated gene transfer of HSV- tk gene was reported in a mouse model using an albumin promoter and an AFP enhancer (82). Further work by the same group also reported therapeutic efficacy and a bystander effect of AAV-mediated intra-tumoral delivery of the HSV-tk gene followed with treatment using GCV (83). Interestingly, in additional experiments, the same group also reported an enhancement of tumor cell killing with a rAAV containing the HSV-tk gene along with IL-2 gene compared with transduction of vector containing only the HSV- tk gene (84). Thus, it is possible to enhance antitumor effects by delivering two different therapeutic genes in the same vector. Although there is a size constraint in the packaging of foreign genes in rAAV, most of the therapeutic genes in the context of cancer therapy are well within the packaging limits of rAAV either alone or in tandem. Similar in vivo therapeutic effects of AAV-mediated delivery of the HSV-tk gene have also been reported in an experimental glioma model (85).

Consideration of molecular chemotherapy strategies for selective killing of tumor cells suggests that long-term expression of transgenes is not an imminent requirement; hence, AAV-based vectors are less preferred over adenoviral vectors. Further, the efficacy of adenoviral infection in different tumor cells has been reported to be significantly higher than many other available gene therapy vectors. However, it has recently been reported that the efficiency of rAAV transduction of primary tumor material, derived from malignant melanoma and ovarian carcinoma, is significantly higher (>90%) than that seen in established tumor cells of the same derivation in culture (86). This observation suggests that it is possible to utilize rAAV in direct targeting of tumor cells for an effective killing by approaches such as molecular chemotherapy, cytokine gene transfer, and inactivation of protooncogene expression. In addition, studies by Su et al. using an AAV-TK-IL-2 vector reported disappearance of the rAAV genome following GCV treatment and regression of the transduced hepatocellular carcinoma (84). Although a proportion of rAAV integrates into the host genome, unlike transgene expression, integration of the vector does not occur immediately following transduc-tion. Hence, GCV treatment following vector administration at an early time point should still achieve therapeutic benefit minimizing long-term retention of the transgene. Identification of tumor cell-specific ligands and use of tissue-specific promoters may also allow transduction and transcriptional targeting of rAAV intratumorally. Possible correction of malignant phenotype by rAAV-mediated p53 gene transfer has been reported recently (87) suggesting the efficacy of rAAV-mediated phenotypic correction at a molecular level.

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