Monographs in Virology: Replication-Competent Viruses for Cancer Therapy (Vol 22)

Details:

P Hernaiz Driever and SD Rabkin (eds)
Published by Karger (2001)
ISBN:  3-8055-7248-4. 182 pages plus index.
RRP:  US$148.00


Cancer is primarily a disease arising from random damage to the genes of some somatic cells that confers to them a growth advantage over other cells in the body. In this context, one of the major challenges in the evolution of higher organisms from unicellular bacteria is the need to rapidly distinguish from the healthy cells those cells in a multicellular organism that sustain somatic DNA changes that radically alter the growth properties of the cells. Such cells must then be eliminated in a timely fashion, so as not to endanger the existence of the whole organism. The increasing understanding of the mechanisms of apoptosis is indeed gradually revealing the intricate mechanisms that link the process of apoptosis to DNA damage and the mechanisms of DNA replication, DNA repair and cellular growth. Conversely, each case of cancer testifies on how often these mechanisms of molecular surveillance fail, with disastrous consequences for the individual patient.

An interesting question to consider in this process is how viruses of higher organisms may modify the mechanisms of DNA replication, DNA repair and apoptosis and to what extent the evolution of these viruses could have been shaped by the needs of the host to eliminate damaged cells. Could the mechanisms of bacteriophage excision from the bacterial chromosome when the latter sustains double strand breaks have a correlate in eukaryotic cells? Could the rapid production of many linear molecules of viral DNA in a eukaryotic cell serve a role in testing the ability of the cell to repair double strand breaks in its chromosomal DNA? Or conversely, could some of the common human viruses serve a positive role in the identification and killing of those cells in the body whose DNA repair mechanisms fail and become permissive for uncontrolled viral replication?

Viewed in this context, it seems quite likely that natural selection may have already endowed some human viruses with properties that may be useful for the identification and killing of damaged cells in various tissues before they can give rise to cancer. Furthermore, a specific type of cancer that may escape the endogenous molecular surveillance mechanisms that may exist in a certain cell type still may be susceptible to killing with some viruses. However, the balance between good and harm with many wild-type viruses may often be too close to allow useful clinical application. Genetic engineering of such viruses may be necessary before they can be employed usefully for cancer therapy.

The book by Driever and Rabkin reviews practical progress in the use of a number of replication-competent viruses for cancer therapy. Separate chapters review the use of herpes simplex virus, adenovirus, reovirus, parvoviruses, vaccinia virus and Newcastle disease virus. Efforts to genetically engineer wild-type viruses to reduce their potential for harm are described, in parallel with efforts to endow such recombinant viruses with novel strategies for cancer cell killing. Progress in such studies has been slowed down by the limited ability to perform genetic engineering in eukaryotic cells, a situation that is rapidly changing as more and more large viruses are cloned as bacterial artificial chromosomes. Techniques recently developed for the precise genetic engineering of large genomic DNA fragments in bacterial artificial chromosomes are being used to remove undesirable genes from the genomes of large human viruses, while endowing them with new genes targeted to limit tumour growth.

This book fails to place such efforts in the context of a theoretical framework that argues in favour of the cautious use of common viruses for cancer therapy. Similarly, although the potential for harm through unwanted virus/host interactions receives ample consideration in the book, there is no consideration of any possible interactions between attenuated viruses that may be useful for cancer therapy and other endogenous viruses that may be co-infecting the same cells. This is indeed a serious omission in the midst of the HIV pandemic, given the high propensity of this virus to integrate and the low sequence specificity of its integration mechanism. The last thing anybody would want to do in the struggle against cancer is to provide HIV with a novel mechanism of transmission by integration of its genome into a large human virus of reduced pathogenicity.

Although this book is restricted in scope, it should be useful not only to the specialists that may be interested in the field of cancer therapy with replication-competent viruses, but for all those seeking novel approaches to cancer therapy by exploiting the natural defence mechanisms against cancer cells.

P Ioannou
Head, Cell & Gene Therapy (CAGT) Research Group
The Murdoch Children’s Research Institute
Royal Children’s Hospital
Parkville, VIC

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