| Abstract: |
intratumoral transfer of prodrug-activating genes has been pursued as a strategy for improving the therapeutic index of chemotherapy agents. We first described the use of the rat cytochrome P450 2B1 gene to provide tumor cell sensitivity to cyclophosphamide (CPA) (Wei et al., 1994). This gene can also provide chemosensitivity to a pro-nitrosourea agent (MPCNU). The proliferation of glioma cells that express the transgene is rapidly inhibited by these prodrugs. The activated CPA metabolite is diffusible, thereby providing bystander killing even at a distance. Antitumor effects can be achieved using retrovirus, adenovirus, or herpes mutants modified to express P450 2B1. Using the median-effect method of Chou, synergetic interactions between CPA and ganciclovir were observed in cells co-expressing the F450 and the TK genes. These results provide a framework for exploiting combinations of prodrug-activating genes to generate more potent antitumor effects. |
