Prodrugs for Gene-Directed Enzyme-Prodrug Therapy (Suicide Gene Therapy)

[摘要] This review focuses on the prodrugs used in suicide gene therapy.These prodrugs need to satisfy a number of criteria. They must beefficient and selective substrates for the activating enzyme, andbe metabolized to potent cytotoxins preferably able to kill cellsat all stages of the cell cycle. Both prodrugs and theiractivated species should have good distributive properties, sothat the resulting bystander effects can maximize theeffectiveness of the therapy, since gene transductionefficiencies are generally low. A total of 42 prodrugs exploredfor use in suicide gene therapy with 12 different enzymes arediscussed, particularly in terms of their physiocochemicalproperties. An important parameter in determining bystandereffects generated by passive diffusion is the lipophilicity ofthe activated form, a property conveniently compared by diffusioncoefficients (log Pfor nonionizable compoundsandlog D7for compounds containing anionizable centre). Many of the early antimetabolite-basedprodrugs provide very polar activated formsthat have limited abilities to diffuse across cell membranes, andrely on gap junctions between cells for their bystander effects.Several later studies have shown that more lipophilic, neutralcompounds have superior diffusion-based bystander effects.Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more activeprodrugs, requiring less prolonged dosing schedules to beeffective. It is expected that continued studies to optimize thebystander effects and other properties of prodrugs and theactivated species they generate will contribute to improvementsin the effectiveness of suicide gene therapy.

[学科分类] 基础医学