Published by Communications and Public Affairs (519) 824-4120, Ext. 56982 or 53338
February 22, 2002
Some cancer therapies may make disease worse, new study says
New research by Canadian and American scientists - including a University of Guelph professor - reveals that some new cancer therapies have the potential to make the condition worse.
The findings appear in the Feb. 22 issue of Science magazine. The research was conducted by Brenda Coomber, a Guelph biomedical sciences professor; Bob Kerbel and Joanne Yu of Sunnybrook and Women's College Health Sciences Centre; Janusz Rak of McMaster University and Dan Hicklin of ImClone Systems, Inc. in New York City.
Their study focused on antiangiogenic therapy, a relatively new cancer treatment that works to reduce tumours by cutting off their blood supply, and the p53 "tumour-suppressor" gene. "It is the body's 'quality control' gene," Coomber said, explaining that p53 regulates cell cycle and cell division. "In a cell that has DNA damage, p53 prevents the cell from dividing by inducing repair of the damage or, if the damage was too great, it allows for 'cell suicide'," she said. But human cancer cells often inactivate this cancer-suppressor gene and the cells accumulate mutations.
What the researchers found is that these mutant cells appear to be less reliant on blood supply than cells with normal p53 function are. So therapies that target the blood vessels in tumours are killing off cells with active p53 genes while the mutant cells survive. "We seem to have found a situation where the treatment may be making the disease progress faster," Coomber said.
Using theories that Coomber helped develop while on a research sabbatical at Sunnybrook some years ago, the researchers performed a number of controlled experiments on mice. They compared the resistance of tumours that were derived from human colorectal cancer cells, genetically modified to have either normal or mutant p53 to produce three kinds of tumours: those containing cells with only normal p53; those with cells containing ly inactive or mutant p53; and tumours containing a combination of cells with either p53 gene. Antiangiogenic therapy was used to treat all three types of tumours. "This allowed for direct comparisons between the effects of p53 active and inactive genes, because that is the only genetic difference between the two cell types," Coomber said.
The study found that although the growth of all tumours was inhibited by the treatment, there was a "dramatic difference" in the response based on the p53 status. Tumours that had only cells with active p53 genes increased twofold in size, compared with a sevenfold increase for tumours with cells containing inactive p53 genes.
The researchers further analysed the "mixed-cells" tumours using a special dye that stains the tumours cells closest to the blood vessels a brighter colour. They then broke up the tumours and examined where the p53 mutant and p53 normal cells were located. Consistent with the findings of tumour growth, these tests found that the cells closest to the blood vessels were those with active p53 genes. "These 'mixed tumours' started out having a cell ratio that was about 50:50 in terms of having active and inactive p53 genes. After the treatment, the ratio of wild-type p53 genes dropped to less than 25 per cent," Coomber said.
"The thinking with antiangiogenic therapy is that if you cut off the blood supply to the cell, it cannot get any oxygen and it will die. But this shows that these mutant cells are preferentially able to survive probably because they are much less dependent on the blood supply."
Coomber added that there are caveats, including the fact that the research was conducted in an artificial environment with modified human cancer cells. "But it does means that we should think more about how we approach cancer treatment and that we need additional studies." She added that the findings are not "anti-antiangiogenic."
"There is no magic bullet for treating cancer, but that doesn't mean we cannot have an arsenal of weapons, and this therapy can still be an important one. But what this research is telling us is that thesystem is far more complicated than we could imagine, and we cannot ignore the biology."
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