In order to carry out their mission of producing new infectious copiesof themselves, viruses need to replicate once they are inside cells. Asa result, actively dividing cells are often the ones most affected byviral infection. But viral infection can also kill cells.

These two aspects of viral infection are dramatically illustrated inAIDS patients where rapidly dividing, HIV-infected T cells die.

Viral infection is believed to be associated with the onset of somecancers. However, because cancer cells often divide at a high rate,some viruses that kill cells have the potential of being effectivecancer therapeutics. These viruses would act by virtue of theirpreferentially killing cells in the rapidly growing tumor.

In an article published in the Feb. 27 Proceedings of the NationalAcademy of Sciences entitled, "Comparison of geneticallyengineered herpes simplex viruses for the treatment of brain tumorsin a SCID mouse model of human malignant glioma," herpes simplexvirus (HSV) is examined for its potential as a so-called "oncolytic"virus that kills tumor cells.

Renee Chambers and colleagues from the University of Alabama atBirmingham and the University of Chicago used a severe combinedimmune deficient (SCID) mouse model system in which humanmalignant glioma cells can grow and cause death. These investigatorsintroduced a genetically engineered HSV into these mice to combatthe spread of glioma cell cancer.

Engineered Simplex Infects, But Does Not Spread

Two engineered versions of HSV were used in these studies: one inwhich the G134.5 gene was deleted and one in which a stop codonwas inserted into the gene, thus truncating the gene product. NeitherHSV variant multiplied or spread in the non-dividing cells of thecentral nervous system of mice.

By injecting these HSV variants along with human malignant gliomacells into SCID mouse brains, these investigators showed that theycould prolong survival in a dose-dependent fashion. Median survivaltime increased from 15 to 21 days when the HSV constructs wereused. However, all mice injected with glioma cells eventually died.

These scientists showed that the HSV variants were able to infect theglioma cells in cell culture. Cell death was caused by the engineeredHSV because it was unable to prevent a cellular stress response thatis induced by the beginning of viral DNA synthesis. Because thisresponse was triggered, protein synthesis was completely andprematurely shut off. This resulted in cell death and significantlyreduced viral yields.

Variants Distinguish Normal From Neoplastic Cells

As senior author Bernard Roizman, a viral oncologist at theUniversity of Chicago, told BioWorld Today, "We were able to showthat it is possible for viruses to differentiate between normal andtumor cells. The challenge now is to develop new and betteroncolytic viruses. Right now, we have no industrial partnerships; weare just making newer virus constructs. Eventually, we hope to beable to move from mice to humans."

Saul Silverstein, a microbiologist at Columbia University MedicalSchool, commented that, "These investigators have made a goodstart, but there is a long way to go yet. Clearly, these constructs donot work well when the tumor is established. While survival of themice is prolonged, the efficacy of the treatment is not good."

Silverstein said, "The advantage of using HSV instead of retrovirusesis that higher titer, more stable viral stocks can be developed. Mostimportantly, as a `proof-of-concept,' these investigators have beenable to show that their constructs only attack tumor cells and do notspread throughout the central nervous system."

As to the future, Silverstein said, "Although their survival isprolonged, the mice die anyway even with this intervention.However, as Roizman's group points out, gliomas are so bad that anypotential for improvement is encouraging. Oncologists and surgeonstell me that even prolonging life for six months in glioma patientswould be a vast improvement." n

-- Chester Bisbee Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.