Swiss scientists say they've shown that a modified, inactivated adeno-associated virus (AAV) can selectively kill cancerous cells that have a faulty gene. If the gene worked properly, it would keep the cells from dividing unchecked.
Mutations in the gene, called p53, are present in nearly every form of tumor, so a successful method of selectively destroying cells with the malignant errors would be a valuable addition to the anti-cancer armory, experts say.A review of the work appears as a research letter in this week's issue of the journal Nature. Research letters don't carry the same weight as a full, peer-reviewed study, but they are useful ways for scientists to have preliminary findings published.
A so-called tumor suppressor gene, p53 makes a protein called a "transcription factor" that regulates cell division. But in cancerous tissue, p53 often is handcuffed by a glitch that shuts off the gene. Tumors with a faulty p53 gene have turned up in the brain, breast, bone, prostate and other organs in the body.
Cancer researchers are pursuing a number of treatment strategies targeting p53. Some hope to eradicate tumors by replacing their flawed version of the p53 gene with a normal copy. Others have suggested creating molecules that latch on to and correct the mutant p53 gene.
The latest work offers an entirely new approach.
Kenneth Raj and his colleagues at the Swiss Institute for Experimental Cancer Research in Epalinges created a harmless AAV carrying a single strand of genetic information, or DNA, with two "hairpin" twists on each end. They first tested the virus on cells in a lab dish and saw that in those cells with normal p53, the virus halted their division at a phase called G2. The cells then took a day or so to purge themselves of the genetic material from the virus.
But when cancer cells with mutant, inactive p53 were infected with the virus, a "damage control" program caused the cells to kill themselves.
Raj's group also found that treatment with the virus blocked tumor growth in all but 17 percent of mice injected with cancer cells, while all of a group of untreated rodents developed malignancies. The treatment did not appear to harm healthy tissue.
The Swiss scientists say AAV kills cancer cells not by creating a toxic protein but rather by its shape. The hairpin structure kicks off the damage-clearing reaction that "in the absence of active p53, leads to cell death," they write. "Thus viruses can be used to deliver DNA of unusual structure into cells to trigger a DNA damage response without damaging cellular DNA and to selectively eliminate those cells lacking p53 activity."
Dr. Francesco Turturro, a staff scientist at the Human Gene Therapy Research Institute in Des Moines, Iowa, says the Swiss group has gotten around a major problem with gene therapy: namely, how to accurately target only those cells that should be killed while leaving normal ones intact.
But Turturro, the first researcher to show that a cold virus bundled with normal p53 could shrink lymphoma in mice, says there's still the matter of whether a given vector -- a viral delivery system for gene therapy -- will attack every tumor cell it's supposed to.
"The problem for classic gene therapy is that you can't guarantee that when you use any sort of viral vector all the cells in the tumor will get it," he says.
That makes anything but local treatment -- such as direct injection into a skin tumor -- extremely difficult, although Turturro says "we probably can still have some success" with system therapy.
Michael Mackey, a biophysicist at the University of Iowa who studies p53, says the Swiss research could be an important finding for cancer patients. But he says it's crucial to find out precisely how the p53 gene operates during cell growth and division and how many, if any, mutant cells would be left over from a viral treatment that targets the gene.
"It only takes one cell in a billion to transform and form a tumor," Mackey says.