Abstract
This review focuses on the prodrugs used in suicide gene therapy.
These prodrugs need to satisfy a number of criteria. They must be
efficient and selective substrates for the activating enzyme, and
be metabolized to potent cytotoxins preferably able to kill cells
at all stages of the cell cycle. Both prodrugs and their
activated species should have good distributive properties, so
that the resulting bystander effects can maximize the
effectiveness of the therapy, since gene transduction
efficiencies are generally low. A total of 42 prodrugs explored
for use in suicide gene therapy with 12 different enzymes are
discussed, particularly in terms of their physiocochemical
properties. An important parameter in determining bystander
effects generated by passive diffusion is the lipophilicity of
the activated form, a property conveniently compared by diffusion
coefficients (log P for nonionizable compounds
and log D7 for compounds containing an
ionizable centre). Many of the early antimetabolite-based
prodrugs provide very polar activated forms
that have limited abilities to diffuse across cell membranes, and
rely on gap junctions between cells for their bystander effects.
Several later studies have shown that more lipophilic, neutral
compounds 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 active
prodrugs, requiring less prolonged dosing schedules to be
effective. It is expected that continued studies to optimize the
bystander effects and other properties of prodrugs and the
activated species they generate will contribute to improvements
in the effectiveness of suicide gene therapy.