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Oncolytic Viruses and Cancer Therapy

© David Olle

The use of viruses to preferentially infect and kill cancer cells while not harming healthy cells has been studied for at least 50 years. Although early results were disappointing, recent advances in virology and molecular biology techniques have resulted in a revival of interest in the field. This method of cancer therapy is called the use of “oncolytic viruses”, since oncolytic refers to lysis or breakdown of cancer cells through the process of apoptosis. The use of viruses in this type of therapy is different from their use in gene therapy. In gene therapy, the virus is a delivery vehicle, needed to bring a corrective gene or chemotherapeutic agent into the cancer cell. This method is also different from the use of cancer vaccines, which stimulate the body’s natural immune response to destroy the cancer. In fact, an immune response to an oncolytic virus is undesirable, as the virus could be destroyed before it is able to infect the cancer cells.

Researchers have developed many methods of oncolytic virus therapy. All methods involve the virus becoming active in cancer cells that have specific genetic and metabolic transformations. Since most cancers are the result of defective functioning of the p53 tumor suppressor gene, or activated ras or myc oncogenes, most of the research effort is focused in this area. The following are examples of promising treatments.

Adenovirus

Adenoviruses are a group of many viruses that can cause a variety of respiratory and eye infections. In order to multiply, the adenovirus enters the cell, and takes steps that result in the activation of the cell cycle. The functioning of the cell cycle results in the replication of viral DNA. However, this “unscheduled” synthesis of foreign DNA activates the p53 gene, whose function is to maintain the integrity of the cell’s DNA. The p53 then acts to halt the cell cycle. If the DNA cannot be repaired, p53 initiates steps that results in apoptosis, or programmed cell death.

Through genetic engineering, researchers have developed mutant adenoviruses that can only replicate in cells with defective p53. In a creative solution, Ramachandra and associates 5 modified an adenovirus so that an antagonist of a transcription factor that promotes DNA synthesis will only be activated in the presence of p53. Therefore, the adenovirus will only multiply in cancer cells with defective p53 gene, while normal cells will be protected from infection.

Herpes Simplex Virus

Lesions on the skin and mucous membranes of the mouth, face, eyes or genitalia characterize herpes simplex virus infection. Researchers have engineered a herpes simplex virus that is non-pathogenic by removal of the gene that codes for ICP34.5 protein. Interestingly, this engineered virus now infects malignant glioma (brain tumor) cells. It turns out that these cancer cells have an activated ras metabolic pathway that the virus uses as an alternate pathway to accomplish replication. The results of a Phase I clinical trial using this modified virus has recently been reported. 3 Although the primary objective of this trial was to study safety (no toxicity or major adverse effects were noted), there was evidence of inhibition of tumor progression and even tumor shrinkage.