Dr. Leisa Johnson and colleagues at Onyx Pharmaceuticals have created a virus called ONYX-411 that targets and kills a broad array of human tumor cell types without harming healthy cells. Their research is presented in the May issue of Cancer Cell.

Cold viruses work by infecting a host cell and then using the cell's own genetic machinery to make so many copies of itself that the cell eventually explodes, releasing progeny virus to infect neighboring cells.

To complete this process in a normal cell, the virus must overcome some of the cell's natural defenses. One such defense, called the retinoblastoma tumor suppressor protein (pRB) pathway, is known to be defective in nearly all human cancers.

The scientists made use of this by making ONYX-411 effective only in cells with defective pRB. This made the virus ineffective in normal cells but deadly to cancer cells.

The effectiveness of ONYX-411 was demonstrated on a broad range of human tumor cell types grown in the laboratory, including cancers of the lung, colon, prostate, breast, cervix and head and neck. Further, the researchers found that mice receiving relatively high doses of ONYX-411 administered intravenously did not exhibit liver toxicity and survived longer due to tumor regression.

Using a specially engineered virus to treat cancer is not an entirely new concept. A predecessor of ONYX-411, called ONYX-015, is currently being used with success in clinical trials. However, ONYX-411 appears to be a significant improvement in that it has a retooled design that makes it more selective and less toxic.

The authors suggest that the lack of viral gene expression in normal cells also makes ONYX-411 an excellent delivery vehicle for anti-tumor genes that will add to its cancer fighting properties.

“The tumor-selective properties of ONYX-411 will allow us to systemically deliver therapeutic genes selectively to tumor cells, thereby reducing the global toxicity and unwanted side effects that plague patients who receive traditional chemotherapeutic approaches,” explains Dr. Johnson.

While this second generation of therapeutic viruses holds much promise as a broad-based cancer therapeutic, the researchers caution that further examination of the effect of repeated intravenous virus administration is called for.

(Reference: Selectively replicating adenoviruses targeting deregulated E2F activity are potent, systemic antitumor agents. Leisa Johnson, Annie Shen, Larry Boyle, John Kunich, Kusum Pandey, Marilyn Lemmon, Terry Hermiston, Marty Giedlin, Frank McCormick and Ali Fattaey. Cancer Cell Volume 1 Number 4 • May 2002)


[Contact: Dr. Leisa Johnson]

21-May-2002