TORONTO, Canada--For years, scientists have known that defective genes allow tumors to grow. Today, researchers blame as many as 30% of all cancers on just one of those genes, the ras gene, the first oncogene discovered in human cancers. Animal research presented at the meeting of the American Association for Cancer Research (AACR) may someday lead to cancer drugs that can block the effects of this oncogene in humans.
The ras gene plays a pivotal role in cell biology, Saïd M. Sebti, PhD, said at a media conference held in conjunction with the AACR meeting. The gene acts as a controller--a dispatcher that passes on biochemical signals to cells. The signals, in the form of proteins, tell the cell when to divide and when to stop dividing.
Scientists believe that when the normal form of the ras gene is somehow damaged, whether through exposure to a carcinogen such as cigarette smoke or through a spontaneous biochemical mistake when the cell replicates, the protein ultimately manufactured by the defective, mutated form of the ras gene is a permanently switched-on protein that defies signals to stop cell growth. The result is continuous, unstoppable cell division and tumor enlargement.
Dr. Sebti, associate professor of pharmacology, University of Pittsburgh, said that his team, in collaboration with the team of his colleague Andrew D. Hamilton, PhD, professor of chemistry, has successfully designed and tested in mice a new class of compounds that selectively block the function of the mutant ras gene.
He noted that the ras protein has to become hooked to the underside of the cell membrane. If it does not become anchored in this way, the mutant ras protein stays in the cell's interior and stops functioning, so there is no rampant cell division.
The University of Pittsburgh researchers found that nonpeptide peptidomimetics can be used to selectively block mutant ras gene activity. These agents mimic peptides in the way that they interact with farnesyl transferase, the enzyme that helps the ras protein attach to the cell membrane, Dr. Sebti said.