David H. Kirn, Editor virus, their expression may be orchestrated to occur simultaneously or serially, at levels that will maximize their therapeutic benefit. Expressing transgenes serially, at different times in the viral lytic cycle, is of greatest value early in treatment when the infection may be more synchronized. As a viral infection spreads and encounters a heterogeneous tumor cell mass, it will likely become asynchronous, although the relative expression of different transgenes may still be maintained. With its longer life cycle and more widely spaced periods of IE, E, and L protein expression, Ad may be better suited than HSV for the serial expression of transgenes.

Endogenous viral promoters can also be used to restrict transgene expression to tumor cells. Thus, if the early events of viral infection—attachment, penetration, IE, or E expression—can be restricted to tumor cells, normal cells will not support viral DNA replication and will not be lysed. Similarly, substituting a therapeutic transgene for a late gene that depends on viral DNA replication for expression should restrict transgene expression to productively infected tumor cells.