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The Design of Selectively-Activated Prodrugs for Cancer Chemotherapy



Tumor-selective activation of anticancer prodrugs is of increasing interest, given several new concepts for such activation which have recently emerged. These include chronic hypoxia and low external pH as consistent properties of solid tumor tissue, and new antibody- and genetic-based methods for specifically delivering activating enzymes to tumors. Such prodrugs are conceptually considered as comprising three separate domains (a trigger which determines the tumor-selective activation, an effector which provides the cytotoxic event following trigger activation, and a linker
mechanism which deactivates the effector in the prodrug and efficiently transmits the activating signal). This concept allows independent consideration of the types of structures most suitable for each domain, and the criteria which they must meet. The existing classes of compounds designed as selectively-activated anticancer prodrugs are reviewed, showing that the primary design criterion for the effector unit is high cytotoxicity, whereas the requirements of trigger units depend critically on the mode of selective activation.
