| Abstract: |
Background: Worldwide, the liver is the commonest site of primary and secondary cancer, yet the large majority of these tumours have hitherto been incurable. Recombinant viral gene therapy provides a novel method of attacking liver tumours, either by delivering noxious agents directly to the target or by replicating inside the tumour to destroy it from within. Methods: This review discusses the different types of viral strategy, the viral agents that are employed and the specific methods of gene therapy directed against liver tumours. Results: The most promising viral strategies are as follows: (1) suicide gene therapy, in which a prodrug is converted into a toxic form by cancer cells that have been transduced by a gene that encodes for an activating enzyme; (2) replacement of deleted or mutated p53 gene; (3) immunomodulation of the tumour by cytokines that have been introduced by a viral vector; (4) oncolytic therapy using viruses that have been attenuated by strategic gene mutation but retain their antitumour activity. Three main types of virus have been used in this therapy: retroviruses, which integrate their genome into the chromosome of dividing cells, adenoviruses, which have high transduction efficiency and are very immunogenic, and herpes simplex viruses, which selectively replicate within the tumour cell and cause death by cell lysis. Suicide gene therapy using either an adenoviral or a retroviral vector has shown promising results against experimental tumours in vivo. The same two vectors have been used to replace mutated p53 in the treatment of hepatocellular carcinoma and colorectal cancer metastases in Phase I clinical studies. Both adenovirus and retrovirus can deliver interleukin-2 to liver cancer cells, with effective reduction in tumour burden and lasting immunity; interleukin-12 has also been investigated in this regard. Viruses are naturally cytolytic, and there is growing interest in engineering them to express differential toxicity to tumour and natural tissue. Herpes simplex virus mutations (hrR3, G207) demonstrate powerful oncolytic activity against colorectal cancer cell lines, and likewise the adenovirus mutant ONYX-015. Early trials are under way in patients with liver metastases. Conclusions: These several strategies offer a new and exciting method of treating liver tumours that are unsuitable for surgical resection or are resistant to other conventional therapies. This is a rapidly developing field, and a great deal of work is required to determine the safest and most effective means of treating liver cancer by means of viral agents. |
