Most cases of
cancer, when detected at an advanced stage, cannot be cured with conventional therapeutic modalities. Therefore, novel targeted approaches such as gene therapy are needed. Nevertheless, while the safety record of gene therapy for
cancer has been excellent with more than a thousand patients treated without mortality related to the
therapy, clinical efficacy has so far been limited. Moreover, it has become evident that clinical efficacy is partly determined by efficacy of gene delivery. Most adenoviruses used for gene therapy have been based on serotype 5 (Ad5). Unfortunately, recent data suggest that the primary receptor, the
coxsackie-adenovirus receptor (CAR) expression in
tumors may be highly variable resulting in resistance to
adenovirus infection. Consequently, various strategies have been evaluated to modify adenovirus tropism in order to circumvent CAR deficiency, including retargeting complexes or genetic capsid modifications. To further improve
tumor penetration and local amplification of the anti-
tumor effect, selectively oncolytic agents, e.g. conditionally replicating adenoviruses (CRAds), have been constructed.
Infection of
tumor cells results in replication, oncolysis, and subsequent release of the virus progeny. Normal tissue is spared due to lack of replication. This review will focus on a discussion of various modifications of adenovirus to achieve efficient anti-
tumor effect, and special emphasis will be placed on CRAds in multimodality treatments.