The present application describes a novel approach to target chemotherapeutic drugs specifically to tumors. It is based on the ability of spores of certain obligate anaerobes to germinate and proliferate selectively in the hypoxic/necrotic regions common to solid tumors. The hypothesis being developed is that because these hypoxic/necrotic regions are unique to solid tumors and because the proliferation of the obligate anaerobes only occurs in the tumor, then any proteins expressed by the bacteria will be present only in the tumor. This selective expression can be used for targeted activation of prodrugs. It is believed that this strategy has the potential of being more tumor-specific in its targeting than any other strategy presently being investigated. This application will use a genetically engineered strain of Clostridium acetobutylicum as the targeting vector to express enzymes capable of activating specific prodrugs. In the first case, the Clostridium species will be engineered to express E. coli-derived nitroreductase which metabolizes the monofunctional alkylating agent CB1954 and close analogs to bifunctional alkylating agents that are 10(4) to 10(5) times more toxic than the parent compound. Preliminary studies have demonstrated that this nitroreductase can be expressed in active form selectively in mouse tumors. In the second system, the Clostridium will express beta-glucuronidase which is capable of metabolizing glucuronidated conjugates of selected anticancer drugs, including a doxorubicin prodrug. Although the prodrugs to be used will be applied systemically, the toxic metabolites should be generated solely in the tumor. The application is a joint effort of two laboratories with extensive molecular biology and pharmacological expertise.
| Brown, J Martin (2002) Tumor microenvironment and the response to anticancer therapy. Cancer Biol Ther 1:453-8 |
| Liu, S C; Minton, N P; Giaccia, A J et al. (2002) Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther 9:291-6 |
| Lemmon, M J; van Zijl, P; Fox, M E et al. (1997) Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Ther 4:791-6 |
