Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)
One limitation of conventional chemotherapeutic approaches has traditionally been toxicity associated with administration of cytotoxic drugs, given the nonspecific nature of these agents. Gene therapy techniques can be used to either enhance prodrug concentration and effect within tumors or decrease toxic drug effects within normal tissues. Examples include genetic prodrug activating therapy (GPAT), genetic-directed enzyme prodrug therapy (GDEPT), or virus-directed enzyme prodrug therapy (VDEPT), which have the following mechanisms of action:
- Preferential insertion of genetic material into cancer cells that encodes prodrug modif ying enzymes or cofactors
- GPAT uses tumor-specific transcription factors to up-regulate expression of gene products within tumor cells, whereas GDPT and VDEPT rely on vector targeting to deliver genetic information within the tumor environment
- Production of cytotoxic metabolites from administered prodrugs
- Preferential killer of cancer cells with reduced toxicity
Chemotherapy resistance genes
- Chemotherapy resistance genes are introduced into normal tissues (for example, multidrug resistance genes such as MDR-1).
- Gene products cause efflux or detoxification of chemotherapeutics in normal tissues, allowing increased dosages of cytotoxic agents with reduced toxicity profiles.
- Hematopoietic stem cells have been transduced with MDR-1 and then used adoptively with high-dose chemotherapy for relapsed leukemia or lymphoma.
For, example, direct injection of plasmid DNA expressing cytosine deaminase under the erB-2 gene promoter was used in a small trial of breast cancer patients. Production of 5-FU from 5-fluorocytosine was then used in a suicide gene approach to selectively target tumor cells to cytotoxic therapy.