Drugs can cure you and they can kill you. More often, they’ll do something in between. They’ll relieve some of what ails you, but there may be a cost. Side effects can be relatively mild, such as rashes, fever, fatigue, and nausea. Or they can be more severe, including internal bleeding, insufficient numbers of white blood cells, and abnormal heart rhythms. Because so many people rely on drugs, the problem of side effects amounts to a major public health issue. Several recent high-profile reports have suggested that adverse side effects of drugs rank among the leading causes of hospitalization and death in the United States.
So far, prescribing drugs is something of a crapshoot. It’s often difficult to predict who will benefit from a specific drug and who will be susceptible to side effects.
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“The question is, How can we appropriately individualize drug therapy to maximize benefits and minimize risks?” says Francis Collins, director of the National Human Genome Research Institute in Bethesda, Md., the federal agency behind the public sequencing of the human genetic code.
These differences in drug response are in large part genetically determined, Collins says. That diversity provides the basis for one of the most touted potential benefits of genetic knowledge: By teasing out the connections between a person’s genes and his or her drug responses, it may be possible to customize medicine. The science behind this personalized medicine is called pharmacogenetics.
“As you look at developing new therapies, new interventions, and even at the role of nutrition in health, being able to segment populations to see who is benefiting or who is at risk is very important,” says Steven Lehrer, head of DNA Sciences in Fremont, Calif. “Who you are when you’re being treated is the last thing we think of, but it should be the first thing.”
By “who you are,” Lehrer is talking about your genes.
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Genes play an important role in drug response because they dictate how each person’s body breaks down, or metabolizes, medicines. Also, many drugs target particular receptors, which are gene-specified proteins that sit on the surfaces of cells.
These receptors are unique tags that permit substances, including drugs, to bind to cells and sometimes slip inside them. Individual variations in genes affecting metabolism or cell-surface binding can influence responses to drugs.
Last year, a study in the Journal of the American Medical Association (JAMA) considered whether various drugs are metabolized by one or more enzymes that have genetic variants that result in unusually slow breakdown. It found that almost 60 percent of the drugs most commonly cited as triggering adverse reactions fit that description. In contrast, such enzymes break down only 22 percent of drugs within a random sample of those sold in the United States, says Kathryn A. Phillips of the University of California, San Francisco.
“These results suggest that genetic variability in drug-metabolizing enzymes is likely to be an important contributor to the incidence of adverse drug reactions,” Phillips says.
People who break down drugs slowly may suffer problems for two reasons. In some cases, drugs become active only after they are metabolized. If this happens more slowly than usual, or not at all, the person may experience no benefit. In other cases where drugs are not broken down as quickly as anticipated, the effective doses may be much higher than intended.
One of the first widely used applications of pharmacogenetics is within the arena of cancer treatment. In part, this is because most cancer drugs are relatively toxic, so physicians have much incentive to reduce side effects.
Consider the drugs thioguanine and mercaptopurine, which are prescribed for acute leukemia, as well as to prevent rejection of organ transplants. An enzyme called thiopurine methyltransferase, or TPMT, normally inactivates the drugs. About 1 in 300 people does not have an effective version of this enzyme, and about 1 in 10 has one, rather than two, functioning copies of the gene, says William Evans of St.
Jude’s Children’s Research Hospital in Memphis. These groups of people are consequently at high risk of side effects, he says.
Now, Evans notes, U.S. oncologists routinely test patients for TPMT activity before prescribing these drugs. They then give patients with ineffective TPMT only low doses of the drugs. “It’s the first pharmacogenetic test to make it all the way into the real world, into the clinic,” he notes.
Other metabolizing agents that are being carefully examined are a large family of enzymes called cytochrome p450s. These enzymes, which are made in the liver, break down nutrients from food and metabolize up to half of all drugs now in use.
Scientists have reported hundreds of possible links to these enzymes. For example, the commonly prescribed anticoagulant warfarin is primarily broken down by a cytochrome p450 called CYP2C9. About 18 percent of people have a variant of the CYP2C9 gene that slows their metabolism of the drug, says David Veenstra of the University of Washington in Seattle. Among patients getting warfarin because of irregular heart rhythms and other conditions, those with slow-metabolizing variants of CYP2C9 are more susceptible to side effects, such as severe internal bleeding.
Today, physicians monitor patients receiving warfarin by testing their blood clotting. Veenstra says that it takes doctors longer to establish an effective and safe dose of warfarin in patients with the CYP2C9 variant than in other patients, so these patients may be at increased risk of side effects. He and his colleagues reported their results in the April 3 JAMA.
A genetic test might help doctors find the correct dose. However, Veenstra adds, in this case, newer, safer anticoagulants may eliminate the need for pharmacogenetic testing.
You’re OK, I’m OK
In addition to affecting how a specific person metabolizes drugs, genetic variations also encode other molecules at the biochemical center of many diseases. Variations in those genes open avenues for more personalized medicine.
For example, researchers monitoring patients with hypertension found that more than a third had a specific variant in a gene that encodes the structural protein alpha-adducin. This variant leads to excess salt retention in their kidneys. People with the alpha-adducin variant were twice as likely to avoid serious side effects, including heart attacks and strokes, if they took diuretics than if they took other types of antihypertension drugs. Diuretics’ effect of reducing salt retention probably explains the boost in beneficial effect, notes Bruce Psaty of the University of Washington. He and his colleagues published their data in the April 3 JAMA.
Monitoring variants of several genes involved in inflammation, lipid metabolism and transport, and drug metabolism may help physicians predict the effects of cholesterol-lowering drugs called statins, says Antonio Gotto, dean of the Weill Medical College of Cornell University in New York. “The medical community has been aware of clinical and metabolic differences among the statins, but now, for the first time, we have some genetic evidence that begins to explain these differential effects,” he says.
Genaissance Pharmaceuticals in New Haven, Conn., has funded a study that begins to map out responses to different statins. Similar work is under way for treatments for asthma and HIV infection.
Many drugs, such as common antibiotics and allergy medications, have been pulled from the market because they trigger abnormal heart rhythms in some people. Among patients who experience drug-induced heart-rhythm abnormalities, Dan M. Roden of Vanderbilt University School of Medicine and his colleagues found, 10 to 15 percent had gene variations previously linked to an inherited abnormal heart rhythm called torsades des pointes. These variations were absent in people who hadn’t had drug-induced heart problems. Screening for these gene variants might enable some of these antibiotics and allergy drugs to stay on the market, he concludes.
Eventually, genetic markers might help doctors match patients and drugs “in such as way that we can achieve the beginnings of personalized medicine,” says Gualberto Ruao, chief executive officer of Genaissance. “We see this as the end of trial-and-error in medicine.”
Getting personal with cancer
The hottest area of pharmacogenetics may be in better tailoring treatment to specific cancer types. For example, Herceptin and Gleevec are two drugs that only affect cancerous tissues expressing certain genes.
Herceptin binds to a protein that stimulates rapid tumor growth. This substance is present in excess in about a third of breast cancers. Before prescribing the drug to their patients, doctors can test how many copies of the gene for HER2/neu, which encodes this protein, are present or measure concentrations of the protein itself. Patients without the excess HER2/neu protein or its gene wouldn’t receive the drug.
Gleevec takes advantage of a particular enzyme that is mutated in a few rare cancers, such as chronic myeloid leukemia. When Gleevec blocks the mutated enzyme, growth of the cancer cells stops, but the drug has minimal effects on healthy dividing cells (SN: 5/26/01, p. 328: Available to subscribers at New drug takes on intestinal cancer).
Scientists are also turning to large-scale screens of gene activity–hundreds of genes simultaneously measured on single chips called microarrays–to better classify cancers (SN: 4/8/00, p. 239). Microarrays can differentiate among types of leukemia that aren’t distinguishable under a microscope.
Increasingly, studies suggest that gene-activity scans can identify which cancers are most and least likely to respond to treatment. Using microarrays to classify cancers is faster than the conventional methods of distinguishing cancer subtypes–and in treating cancer, time is often of the essence, says Evans.
In the June 20 New England Journal of Medicine, researchers at the National Institutes of Health reported that DNA microarrays could tease out three subgroups among patients with diffuse large-B-cell lymphoma, a kind of blood cancer. By looking at which of 17 genes were active in each cancer, the researchers could successfully predict whether it was likely to be susceptible to different regimens of chemotherapy.
Similarly, Evans’ colleagues at St. Jude’s reported in the March Cancer Cell that, among children with acute lymphoblastic leukemia, gene activity patterns identified all the known subtypes of the disease–which respond differently to various therapies. Further, within some of these subsets, gene-activity profiling with microarrays can even discriminate between those who will remain free of disease after treatment and those who will relapse.
Now, other researchers are finding that gene expression varies within subtypes of a variety of cancers, Evans says. And those differences mean “you can predict outcome not just in blood cancers but in brain tumors, neuroblastoma, acute myelogenous leukemia, ovarian cancer, and prostate cancer,” he adds.
Evans notes that the biggest question remains: Can you avoid a bad outcome by using genetic information to select therapies? “We don’t know that yet,” he says, “but that’s the hope.”
The future of individualized medicine
If, or when, pharmacogenetic tests become common, ethical questions will begin to crop up, Evans notes. “Privacy is a very important issue for all genetics testing,” he says.
Most researchers and ethicists agree that there are fewer ethical concerns about pharmacogenetic screening, whose ultimate aim is more effective treatment, than about types of screening in which people are tested for disease-causing mutations.
Nonetheless, the possibility remains that patients with gene variants that predispose them to side effects or to forms of disease that would be expensive to treat might have difficulty obtaining health-care coverage.
Even as doctors, patients, insurance companies, and regulatory agencies sort out those issues, the nascent field “arguably has already had a big impact on drug development,” says Roden. Many companies now conduct lab tests to see whether their drug compounds affect common metabolic pathways such as the cytochrome p450 enzymes, he notes. If so, these drugs are often pulled from development because they may interfere with the breakdown of other drugs that a patient may be taking.
Many drug companies are banking on the idea that pharmacogenetics will lead to safe, effective drugs. Furthermore, says Lehrer, pharmaceutical companies are screening people enrolling in clinical trials for a variety of genes suspected to play a role in drug metabolism or action. If a drug turns out to have side effects only in one group of people, or to be effective in only one group of people, pharmacogenetic tests may help companies get these drugs–which otherwise might be dropped from development–into the marketplace.
“The real hope is that down the road, you’ll have a gene card that says what your risks are, a genetic profile that says how you are likely to respond to a variety of exogenous stressors, like mental stress, drugs, aging, diet,” Roden says.
Researchers agree that this possibility is quite a ways down the road, but they are quick to point out that personalized medicine is worth the wait.
Comments on this article are welcome. Contact Ivars Peterson at firstname.lastname@example.org.