The potential advantage of inhibiting the cell cycle in diseases marked by cell proliferation is fairly intuitive, and such an approach has not escaped the notice of the biotech industry.
Flavopiridol is a cell-cycle inhibitor that is in Phase I and II trials jointly sponsored by Aventis Oncology, part of the Paris-based Sanofi-Aventis Group, and the National Cancer Institute in Bethesda, Md.
In research reported in the June 7, 2005, issue of the Proceedings of the National Academy of Sciences, scientists from Georgetown University Medical Center in Washington and the Universita di Pavia in Italy tested whether cell-cycle inhibition could be a useful strategy in another condition, which, at first blush, has less to do with cell proliferation and more with cell death - brain injury.
Though the results in the new area are exclusively derived from animals, they do look encouraging; senior author Alan Faden, professor of neuroscience, neurology and pharmacology at Georgetown University Medical Center, called the drug "effective to a level we've not seen in nearly 30 years of trauma research."
Interestingly, the researchers demonstrated effects of cell-cycle inhibition even in cells that no longer divide. The neurological symptoms of traumatic brain injury primarily are caused by the death of neurons, which by and large no longer divide in adults, but still respond to activation of the cell cycle - via suicide. "If you activate the cell cycle in cells that are no longer able to divide, it causes apoptotic cell death," Faden told BioWorld Today.
But two other cell types, which do continue to divide in adults, also are involved in the damage. Astroglia are a type of support cell that contribute to scarring of the injured area after brain injury, which inhibits regeneration. Another cell type, microglia, produces pro-inflammatory proteins after injury, which also inhibit recovery. In astroglia and microglia, activating the cell cycle induces proliferation, which could contribute to scarring and inflammation. Since all three mechanisms contribute to the final neurological effects of brain injury, treatment with a cell-cycle inhibitor potentially could affect neurological outcomes on several fronts.
In the current research, the scientists first used microarray studies to determine whether cell-cycle associated-genes are up-regulated in rats after inducing traumatic brain injury. They found such up-regulation both in nondividing neurons and in still-dividing astrocytes and microglia.
In cell culture experiments with neurons and astrocytes, the researchers used three agents that inhibited the cell cycle at different points to test whether they could reverse up-regulation. All drugs tested reduced the up-regulation of cell-cycle proteins and neuronal cell death and astrocyte proliferation, respectively. While they have not yet analyzed whether there are subtle differences in the effects, lead author Simone DiGiovanni told BioWorld Today that "different classes can all have a positive effect. The data show that the effect is not specific to one drug, but is specific to cell-cycle inhibitors."
The researchers then tested whether inhibiting the cell cycle would show benefits when administered after brain injury. Treating animals with flavopiridol shortly after brain injury had remarkable effects, both anatomically and behaviorally. Anatomically, the treatment decreased glial scarring, microglial activation and neuronal death.
"When we looked with MRI, the lesion volume was reduced by over 80 percent, and histologically we couldn't find the hole in the brain that you normally see after injury," Faden said, adding that behaviorally, "motor and cognitive functions were indistinguishable from non-injured controls after 30 days."
The scientists currently are working on experiments that mimic clinical realities more closely. In the PNAS paper, "we gave the drug into the brain ventricle and right after injury," Faden said. Newer experiments, however, suggested that neither of those are necessary for success; in follow-up experiments, when the drug was given intraperitoneally and up to 24 hours after injury, it still had strong effects. Faden summarized that flavopiridol's mechanism "offers a significant window that could allow most patients to be potentially treated."
Faden also noted that while flavopiridol could potentially move through clinical testing quickly because it already is being developed in another indication, it is not the only fish in the sea.
"We'll see whether anyone has the time and the money to develop flavopiridol for brain injury," he said. "But other classes of inhibitors might be effective, as well, and could even provide better brain penetration and side effect profiles."