Friday, March 28, 2008

Myxoma virus: From Rabbits to Cancer

ResearchBlogging.orgMore than half a million individuals in the US died in 2004 from cancer and more than 10.8 million Americans are living with the disease.() The number of cancer deaths each year continues to decline, due to advances in medical technologies. With the advent of a cervical cancer vaccine, this number promises to continue to drop dramatically. Furthermore, there are new treatments in development that promise to revolutionize the effective treatment of cancer. One of these, which I am currently fascinated by, is oncolytic virotherapy. This is a summary of a review article by Grant McFadden at the University of Florida.

Oncolytic virotherapy is the use of live viruses to kill malignant cells in situ. The use of viruses holds potential to not only be a direct treatment of cancer, but also studies of viruses with cancer cell tropisms may help in the development of other treatments and vaccines. Variola virion, similar to myxoma virus from NIH

There is much knowledge regarding the ways that viruses “push” host cells into appropriate stages of the cell cycle to allow a productive viral infection (Adenoviruses, Papillomaviruses, and Polyomaviruses all push non-replicating host cells into S-phase, allowing productive infection). These viruses, therefore, have the ability to not only cause cancer (by the unchecked growth), but also are more able to kill rapidly dividing cells—cancer cells are more susceptible.

A virus called “ONYX-015,” an adenovirus, was the first oncolytic virus tested. Lacking a gene called E1B-55K, this virus can only replicate in cancer cells. E1B-55K serves to block the p53 pathway, thereby allowing the host cell to enter S-phase unchecked. Without E1B-55k, p53 remains active. But in cancers, the p53 pathway is usually inactive; therefore these cells remain susceptible to infection.

This paper discusses the use of a more preferential type of oncolytic virus; one which does not normally infect human cells, but is able to enter productive infection in cancer cells. Specifically, this review describes the use of myxoma virus, a species of poxvirus.

Poxviruses have been known for ages, and have been studied as both vaccines and pathogens. These types of viruses posses a variety of features which are highly desirable to the development of oncolytic virotherapy. 1) Short (24hr) replication cycle 2) Large, easy-to-engineer genome 3)Exclusive replication in the cytoplasm—with no record of any chromosomal integration 4)Highly immunogenic, allowing strong immunity to be formed.

Myxomatosis afflicted rabbit. From www.rnw.nlMyxoma virus causes the highly lethal “myxomatosis” in European rabbits (see photo at left) and is remembered by most as the infamous biocontrol method to decrease rabbit populations in Austrailia. This virus has a highly specific tropism for rabbits and is not known to infect any other vertebrate species, including humans.

Although myxoma virus (and most poxviruses) can attach and enter most mammal cells, it was shown to require the action of a specific pathway (type I IFN). This pathway is turned on specifically in cancer cells. Studies have shown that myxoma virus can infect and kill 70% of all cancer lines from the NCI collection—without a specific tumor cell-type tropism.

Further work still must be done to definitively show the pathway involved. Other work includes examining persistant infection, along with studying delivery methods. However, there is great hope for the use of this virus(and perhaps others down the line) to combat cancer.

Stanford, M.M., McFadden, G. (2007). Myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer. Expert Opinion on Biological Therapy, 7(9), 1415-1425. DOI: 10.1517/14712598.7.9.1415

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