oncolytic adenoviruses effect vs brain tumor stem cells?bc stm cells next?

[Lani]

Oncolytic Adenovirus Effective Against Brain Tumor Stem Cells


NEW YORK (Reuters Health) Sept 24 - The oncolytic adenovirus Delta-24-RGD can destroy brain tumor stem cells and the gliomas they produce in vivo, according to a new report.

"The oncolytic approach is very different from other therapeutic strategies," Dr. Juan Fueyo from The University of Texas M. D. Anderson Cancer Center, Houston, told Reuters Health. "Adenoviruses kidnap the cell and take over of the main critical pathways that govern DNA replication, cell growth, cell proliferation, and cell death."

Dr. Fueyo and colleagues investigated the effects of Delta-24-RGD on four brain tumor cell lines from surgical glioblastoma specimens and on xenografts derived from brain tumor stem cells.

The brain tumor stem cells expressed high levels of receptors for the adenovirus, the authors report, which allowed for efficient viral infection, replication and oncolysis.

A Delta-24-RGD dose of less than 2 pfu/cell induced 50% cell death by 6 days after viral infection in most of the cell lines, the researchers report in the September 19th Journal of the National Cancer Institute.

Treatment of glioma-bearing mice with Delta-24-RGD increased the mean survival time from 38.5 days to 66.3 days, the investigators say, and two of eight mice remained alive without noticeable neurological deficits until they were killed at day 92.

Delta-24-RGD appeared to induce autophagic cell death by way of accumulation of Atg5 and LC3-II protein and autophagic vacuoles, the researchers note. Atg5 was also useful as a marker of the adenoviral wave front of spread and as a cellular indicator of viral activity and antiglioma effect.

"Cancer stem cells are believed to be the responsible for brain tumor recurrence after treatment," Dr. Fueyo said. "Showing that therapies, such as Delta-24-RGD, destroy this critical population of cells increases our hopes for the development of treatments that will radically eliminate the tumor and prevent the recurrence."

"We are now attempting to modify the virus to either anchor in cell surface proteins that are expressed in cancer stem cells, such as CD133, or even in using the promoter of CD133 to lead the expression of adenoviral genes," Dr. Fueyo said. "Thus, the adenovirus will infect or replicate exclusively in cancer stem cells."

"It seems that autophagy is part of the lysis process of the adenovirus," Dr. Fueyo added. "Understanding this process better and its optimization should result in the generation of new viruses with enhanced ability to produce earlier, and with more efficiency, their progeny."

J Natl Cancer Inst 2007;99:1410-1414.