August 2001

From University of Southern California

Scientists look for genetic clues on why drugs’ effects vary

Researchers at the Keck School of Medicine of USC and Washington University School of Medicine in St. Louis have united in a multimillion-dollar mission to uncover how genes influence the effectiveness of drugs from person to person.

"This is a very exciting opportunity," says Heinz-Josef Lenz, M.D., oncologist at USC/Norris Comprehensive Cancer Center, associate professor of medicine at the Keck School and the federally funded project’s lead investigator at USC. "This grant makes our collaboration the cutting-edge instrument for pharmacogenetic research in the world."

Doctors know that small genetic differences can affect whether medicines will work in particular patients, but until recently, researchers have only been able to study the differences in one or two genes at a time.

"Now, we are going beyond that," says Howard L. McLeod, Pharm.D., principal investigator for the project and associate professor of medicine, genetics and molecular biology and pharmacology at Washington University School of Medicine. "We are studying entire gene pathways that appear to be important for a given medication."

The National Institute of General Medical Sciences—part of the National Institutes of Health, or NIH—recently funded the project through a four-year, $6.6 million grant. The investigation represents an emerging area of medicine known as pharmacogenetics.

McLeod, an investigator with Washington University’s Alvin J. Siteman Cancer Center, and his colleagues will focus mainly on "individualized medicine"—how to identify the best choice of medication for each patient. "We will use knowledge of a drug’s action in the design of DNA tests to predict a drug’s effect on that person," McLeod said.

Lenz and McLeod already have joined in research to look at the frequency of small genetic differences, or polymorphisms, among Latinos. Polymorphisms tend to occur at different rates in various ethnic groups, Lenz explains. Because cancer patients at both institutions come from a wide variety of ethnic and racial backgrounds, the researchers are in an excellent position to analyze potential differences in frequencies of polymorphisms in different populations.

The current project focuses on human gastrointestinal cancer, which has varying incidence rates and treatment outcomes in different ethnic groups. Researchers aim to identify and evaluate variations in 95 genes that are involved in the action of the three drugs used today to fight the cancer.

Developing strategies to individualize medicine requires comprehensive study.

Some scientists, for example, must do genetic analysis while others study how minor changes in genes influence a protein’s structure and function. Statistical geneticists are developing ways to assess how changes in several genes are important for individual patients and clinical specialists integrate the genetic information into patients’ treatment.

"The goal of our laboratory is to establish a strong translational research program that uses molecular markers to tailor chemotherapy for each patient," says Lenz, USC/Norris scientific director of cancer genetics.

Relying heavily on the findings and technology of the human genome project, the new endeavor focuses on cancer, said McLeod, "but the strategies we are developing will be applicable to many diseases."

The program is part of a NIH initiative known as the Pharmacogenetics Research Network. "NIH assembled the network to bring together pharmacogenetics scientists across different disciplines and disease areas," says Rochelle Long, a pharmacologist at NIGMS who spearheads the initiative. "Our overall goal is to understand how and why people can have such differing responses to a wide array of medicines."












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