Published Thursday, June 29, 2000, in the Miami Herald
BY RICK WEISS
Washington Post Service
A female surgical patient of Georgetown University physician and pharmacologist David Flockhart presents a classic example of the need for pharmacogenomics.
Pharmacogenomics is a new field of medicine he and others are pioneering that promises to reduce treatment failures by matching medicines with patients' personal genetic codes. After undergoing surgery on her ovaries, she was given codeine, the most commonly prescribed painkiller in America.
"She wanted more and more of the stuff," Flockhart recently recalled. Before long, he said, "she was labeled a drug abuser."
The truth was far simpler. Tests ultimately showed she was among the 7 percent of Caucasians in this country who harbor an inactive form of a gene called CYP 2D6, which helps break down many common medicines, including codeine. Unable to metabolize the codeine into its desired breakdown product, morphine, the woman got no relief.
"Customized prescribing" of drugs will be one of the most important results of the mapping of the human genetic code announced earlier this week, said R. Rodney Howell, chairman of pediatrics at the University of Miami Medical School and president of the American College of Medical Genetics.
Flockhart also had a patient on Prozac who had the same genetic variation, but in her case it led to an effective overdose instead of undermedication. That's because Prozac, like codeine, is also broken down with the help of the 2D6 gene. Since she could not metabolize the antidepressant, the woman suffered an overaccumulation of the drug, with high blood pressure and other side effects.
A patient with tendinitis carries a different gene variant that triggers painful inflammatory reactions in response to so-called quinalone antibiotics.
Scientists know of six common CYP drug-metabolizing genes, all of which operate in the liver and are responsible for breaking down about a dozen different drugs each. They have also begun to find other genes in other parts of the body, which people can inherit in various forms and which can affect how efficiently these people absorb, transport, use and excrete various medicines.
With the recent advent of simple tests that can reveal a person's genetic subtype from a drop of blood or a cheek swab, Flockhart said, "we're beautifully set up to look at variations in these things from person to person. It's a real opportunity to help a lot of people."
In a few settings, genetic testing is already helping doctors inform their prescribing decisions and even save lives.
At the Mayo Clinic in Rochester, Minn., for example, Richard M. Weinshilboum and his colleagues have been using genetic tests to individualize treatments for children with acute lymphoblastic leukemia.
The childhood cancer was universally fatal a few decades ago, but with the advent of a drug called 6-mercaptopurine, more than 80 percent of children can now be permanently cured. In the years since that drug's introduction, though, two questions have plagued doctors: Why doesn't the drug work in every child? Why does it cause serious and even fatal side effects in some? The answers finally arose with the tools of pharmacogenomics.
10 Percent Rate
Mercaptopurine, it turns out, is broken down in the body by an enzyme abbreviated TPMT. But 10 percent of Caucasians and blacks carry a variant of the TPMT gene that renders the crucial enzyme relatively ineffective, and an additional one in 300 of these children lack the gene and the enzyme altogether. (The variant is almost unknown in Asians.) Unable to metabolize the drug, these children essentially overdose on even small doses, and often die from the immune system suppression that ensues.
At the Mayo Clinic and at St. Jude Children's Research Hospital in Memphis, doctors now routinely test for TPMT activity in leukemic children before treating them. Children with especially high levels of the enzyme -- who are, in essence, breaking down the drug before it has a chance to kill their cancers -- are given doses up to 50 percent higher than normal. And those who are effectively overdosing on the drug because of their relatively inactive TPMT genes are getting doses as low as one-fifteenth normal.
One result of the new focus on pharmacogenomics is that old definitions of diseases are breaking down. Cancers, for instance, which have traditionally been classified by their location in the body, are increasingly being typed further by their genetic characteristics and drug sensitivities, and medicines are being developed to take aim at those hallmarks.
Key to Diagnosis
"Now that we have begun to characterize the specific gene patterns of tumors, that is the coming wave of how cancers will be diagnosed," said Kelvin Lee, associate professor of hematology and oncology at the University of Miami/Sylvester Comprehensive Cancer Center.
"You can make good guesses on how a particular tumor will respond to therapy and what kind of disease process you can expect to see," Lee said. "That allows us to make smart treatment choices.
"That accuracy is going to increase logarhythmically," he said. "We're going to be much more capable of treating those cancers in a rational fashion."
Experts predict that in the next few years new genetic tests will show that many other diseases also deserve to be parsed and targeted according to their genetic signatures.
"We're going to learn it's not just 'MS,' or multiple sclerosis," said Kathleen Giacomini, a University of California at San Francisco researcher who is identifying genes that affect drug absorption and transport in the body. "It's going to be MS a, b, c and d. And we can develop new drugs for each of these types."
Herald health writer Christine Morris contributed to this report.