The choice of prodrugs for gene directed enzyme prodrug therapy of cancer

Prodrugs are chemicals that are pharmacodynamically and toxicologically inert but which can be converted to highly active species. In cancer chemotherapy, enzyme activated prodrugs have been effective against certain animal tumours. However, in the clinic it has been found that human tumours containing appropriately high levels of the activating enzymes were rare and not associated with any particular type of tumour. Gene directed enzyme prodrug therapy (GDEPT) attempts to overcome this problem by killing tumour cells by the activation of a prodrug after the gene encoding for an activating enzyme has been targeted to the malignant cell. Here we summarise the various enzyme/prodrug systems that have been proposed for cancer therapy and comment on their suitability for GDEPT. This is because systems developed for other applications such as antibody directed enzyme prodrug therapy (ADEPT) may not be suitable for GDEPT. What is required are nontoxic prodrugs that can be converted intracellularly to highly cytotoxic metabolites that are not cell cycle specific in their mechanism of action. The active drugs released should also be readily diffusible and exert a bystander effect. Alkylating agents best meet these criteria. An example of a suitable enzyme/prodrug system may be a bacterial nitroreductase that can convert a relatively nontoxic monofunctional alkylating agent to a difunctional alkylating agent that is some ten thousand times more cytotoxic.