Tumor-activated prodrugs--a new approach to cancer therapy

Systemic cytotoxic (antiproliferative) anticancer drugs rely primarily for their therapeutic effect on cytokinetic differences between cancer and normal cells. One approach aimed at improving the selectivity of tumor cell killing by such compounds is the use of less toxic prodrug forms that can be selectively activated in tumor tissue (tumor-activated prodrugs; TAP). There are several mechanisms potentially exploitable for the selective activation of TAP. Some utilize unique aspects of tumor physiology such as selective enzyme expression or hypoxia. Others are based on tumor-specific delivery techniques, including activation of prodrugs by exogenous enzymes delivered to tumor cells via monoclonal antibodies (ADEPT) or generated in tumor cells from DNA constructs containing the corresponding gene (GDEPT). Whichever activating mechanism is used, only a small proportion of the tumor cells are likely to be competent to activate the prodrug. Therefore, TAP need to fully exploit these "activator" cells by being capable of killing activation-incompetent cells as well via a "bystander effect." A wide variety of chemistries have been explored for the selective activation of TAP. Examples are given of the most important-the reduction of quinones, N-oxides, and nitroaromatics by endogenous enzymes or radiation; the cleavage of amides by endogenous peptidases; and hydrolytic metabolism by a variety of exogenous enzymes, including phosphatases, kinases, amidases, and glycosidases.