Cancer continues to drive the identification and development of new therapeutic strategies. LeadDiscovery has focussed on a number of these over recent months. Particularly exciting are the endogenous inhibitors of apoptosis; histone deacetylase inhibitors; and the retinoids. Oncolytic viruses represent a further approach to cancer with considerable potential. Although the cytotoxic effects of viruses are usually viewed in terms of pathogenicity, it is possible to harness this activity for therapeutic purposes. In particular, viral genomes are highly versatile, and can be modified to direct their cytotoxicity towards cancer cells. To our knowledge there are almost 20 such oncolytic virus-based therapeutics in development by the pharma/biotech sector. Although most of these are in preclinical development, therapies form Cell Genesys, Crusade, Medigene and Oncolytics are in phase II trial.

Human adenovirus serotype 5 (Ad5) represents a particularly attractive family of oncolytic candidates, showing good efficacy and selectivity for tumor cells. These virus vectors have been modified to replicate preferentially in tumor cells; their oncolytic activity being a natural consequence of the lytic life cycle of Ad5. Field-leaders at the Saint Louis University School of Medicine previously reported on two Ad vectors, KD1 and KD3 that carry two small deletions in the Ad E1A gene. These mutations restrict the replication of KD1 and KD3 to cells with a deregulated cell cycle. These vectors also overexpress the ADP protein, also named E3-11.6K. ADP is an Ad5 protein that facilitates the lysis of the infected cell and the egress of virus from these cells. The Saint Louis group has shown that vectors that overexpress ADP spread from cell-to-cell faster than wild-type Ad5, and that this enhanced vector spread results in improved oncolytic properties of the vector. In addition to the E1A mutations and enhanced ADP expression, in KD1 and KD3 the E3 genes responsible for the down-modulation of the host immune response are deleted. This latter feature decreases the possibility of runaway vector replication. KD1 and KD3 have performed very well in tissue culture as well as in tumor xenotransplant experiments. They obstructed the growth of pre-established subcutaneous human tumor xenografts in nude mice to a level comparable to treatment with wild-type Ad5.

A review of the literature suggested that in in vitro experiments and especially in a clinical setting, the oncolytic effect of tumor-selective replicating Ads can be augmented by the use of concomitant radiation and/or chemotherapy. Following this reasoning, the Saint Louis group tested if the combination of ADP-overexpressing Ad vectors with radiation therapy increased the potency of the vectors. In in vitro experiments, radiation was shown to enhance the ability of KD1 and KD3 to kill tumor cells by a factor of ten to a hundred. In the nude mouse-human tumor xenograft model, KD3 or radiation alone reduced tumor growth by about 5-fold. Combining these two approaches further improved this effect reducing tumor growth by 20-fold. Oncologists and radiation oncologists have been applying a combination of different modalities that allows for lower doses of individual components, thereby reducing the side effects of radiation and chemotherapy while maintaining the efficacy of the treatment. These data therefore suggest that KD3 represents a means of alleviating the side effects associated with using high-dose single-modality anti-cancer treatments.

Entry date Friday, April 11, 2003

Adapted from Toth et al, Cancer Gene Ther 2003 Mar;10(3):193-200 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk