Compounds Block ras Gene Function Compounds Block ras Gene Function

TORONTO, Canada--For years, scientists have known that defectivegenes allow tumors to grow. Today, researchers blame as many as30% of all cancers on just one of those genes, the rasgene, the first oncogene discovered in human cancers. Animal researchpresented at the meeting of the American Association for CancerResearch (AACR) may someday lead to cancer drugs that can blockthe 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 withthe AACR meeting. The gene acts as a controller--a dispatcherthat passes on biochemical signals to cells. The signals, in theform of proteins, tell the cell when to divide and when to stopdividing.

Scientists believe that when the normal form of the ras gene issomehow damaged, whether through exposure to a carcinogen suchas cigarette smoke or through a spontaneous biochemical mistakewhen the cell replicates, the protein ultimately manufacturedby the defective, mutated form of the ras gene is a permanentlyswitched-on protein that defies signals to stop cell growth. Theresult is continuous, unstoppable cell division and tumor enlargement.

Dr. Sebti, associate professor of pharmacology, University ofPittsburgh, said that his team, in collaboration with the teamof his colleague Andrew D. Hamilton, PhD, professor of chemistry,has successfully designed and tested in mice a new class of compoundsthat selectively block the function of the mutant ras gene.

He noted that the ras protein has to become hooked to theunderside of the cell membrane. If it does not become anchoredin this way, the mutant ras protein stays in the cell'sinterior and stops functioning, so there is no rampant cell division.

The University of Pittsburgh researchers found that nonpeptidepeptidomimetics can be used to selectively block mutant rasgene activity. These agents mimic peptides in the way that theyinteract with farnesyl transferase, the enzyme that helps theras protein attach to the cell membrane, Dr. Sebti said.

Nontoxic to Normal Cells

The new inhibitors are considered superior to the peptide-likeinhibitors discovered earlier, because they are not vulnerableto breakdown by enzymes, Dr. Sebti said. The researchers alsoreported at the meeting that the new generation of compounds is1,000 times more powerful than their original compounds developed2 years ago.

The major surprise of their work with the new ras inhibitors,he said, is not so much their potency as their apparent lack oftoxicity to normal cells. Dr. Sebti said that normal cells alsoneed farnesyl transferase for their normal ras gene towork properly. "The side effects are almost nil; it's nature'sluck that normal cells are not affected," he said.

Use of the ras inhibitor strategy has been shown to inhibit thegrowth of human tumors implanted under the skin of mice. Now,Dr. Sebti said, tests are needed of animal models that developtumors in the lung and pancreas.

The first experiments with the compounds on humans may still be2 years away. Even so, he said, "it feels good; it feelslike we're getting there."