Sept. 24, 2008 -- Drug-resistant bacteria, caused by the over-prescription of powerful antibiotics, is bad enough. Now scientists are identifying the genes responsible for drug-resistant cancers, and finding new ways to stop them.
One group of scientists is developing basketball-shaped nanoparticles that would deliver a punch to cancer cells by interfering with their gene expression. The nanotech-inspired therapies are still at least five years away from use in humans, but according to doctors and scientists, stopping drug resistance, instead of creating new drugs, is an important step that will help save lives.
"Most cancers that can't be removed surgically are already drug-resistant or become drug-resistant," said Michael Gottesman, a doctor at the National Institutes of Health. "But a lot of the literature is focused on finding new anticancer drugs, not worrying about resistance to those drugs."
Gottesman recently discovered that one gene, SIRT1, is responsible for up to 50 percent of Cisplatin-resistant cancers. Cisplatin is a common chemotherapy drug used to treat a range of cancers including testicular, ovarian, bladder and lung cancer.
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Drug-resistant cancers develop much the same way drug-resistant bacteria develop. Treating either bacteria or cancer with conventional drugs might kill 99 of 100 deadly cancer or bacteria cells, but that one cell that survives the initial cull can still create a lethal infection or tumor mass.
Some cancers, like some infectious diseases, even start out resistant to drugs, notes Mansoor Amiji, a cancer researcher at Northeastern University.
"Up to 70 percent of ovarian cancers are initially resistant to the first line chemotherapy," said Amiji. "If that doesn't kill the cancer, 100 percent of those who go into remission will be resistant to those drugs."
When cancer returns, or remits, the patient often has more painful and traumatic chemotherapy and a higher likelihood of not being able to fight off the disease.
Cancer cells evolve resistance to drugs in several ways, including blocking the channels drugs use to enter cancer cells or devising more efficient means to pumping them out if the drugs do get in.
The gene SIRT1, for instance, helps cells regulate their metabolism and nutrient intake. Gottesman and his colleagues discovered that expressing the SIRT1 gene slows the cancer cell's metabolism. In essence, SIRT1 allows cancer cells to slow the cell's metabolism, giving them time to collect the anticancer drugs and pump them out of the cell before they do too much damage.
The research was published recently in the journal Molecular Cancer Research.
Identifying the genes responsible for drug-resistant cancer is the first step. The next step is turning them off.
Gavin Robertson, a researcher at Pennsylvania State University, is turning off cancer resistance genes using hollow basketball-shaped nanoparticles called nanoliposomes. The nano basketballs ferry small pieces of RNA (siRNA) that interfere with gene expression into cancer cells.
Once inside, the siRNA silences two mutated genes, B-Raf and Atk3, which together could play a role in up to 70 percent of malignant melanomas, a cancer that can be especially drug resistant. The research appears in the journal Cancer Research.
Gene mutations aren't always identical however, and a drug that targets one person's gene mutation might not work for another. The advantage of an approach like Robertson's is that he could tailor the siRNA molecules to each person's individually mutated, drug-resistant cancer genes. In military terms, that's like moving from World War II-style carpet bombing to modern GPS and laser-guided weapons.
These molecular weapons are still five years away from human use and still await Food and Drug Administration approval, says Robertson, but it could make cancer treatment less painful.
"This would be truly personalized medicine," said Robertson. "We could tailor our drugs to each person's specific DNA to create more effective drugs that have fewer side effects."
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