March 2001

From Washington University School of Medicine

Drug resistance found to vary by ethnicity

New Orleans, March 25, 2001 -- A genetic mutation affecting resistance to chemotherapy occurs more frequently in some ethnic groups than in others according to a new study.

Researchers found that African and African American populations included more individuals with the drug-resistant gene than Caucasian or Asian populations. This might help explain why some people of African descent respond poorly to chemotherapy. The research will be presented March 25 at the annual meeting of the American Association for Cancer Research in New Orleans.

"We now know that the genetic influence on drug resistance is not the same throughout the whole population," says Howard L. McLeod, Pharm.D., associate professor of medicine, of pharmacology and molecular biology and of genetics at Washington University School of Medicine in St. Louis. "Because of this work, we can try to solve the problem."

McLeod, who led the international team of researchers from his previous position at the University of Aberdeen in the United Kingdom, specializes in pharmacogenetics, an emerging research field. Margaret-Mary Ameyaw, M.D., Ph.D., of the University of Aberdeen is the study’s first author and will join the Washington University faculty later this year.

The mutation studied by McLeod and his colleagues changes production of a protein called P-glycoprotein, or PGP, a molecular pump that rids cells of drugs. When working correctly, PGP pumps chemotherapeutic drugs out of tumors, allowing the tumor cells to survive. This response is known as drug resistance. The genetic mutation means the PGP pump stops working, allowing drugs to enter and kill tumor cells.

PGP also rids cells of many other medications, such as HIV protease inhibitors and drugs used to control high blood pressure and prevent failure of kidney transplants.

Working with collaborators in five countries, McLeod and his colleagues did DNA tests on blood samples from 1,280 people from 10 ethnic populations. The researchers studied Ghanaian, African American, southwest Asian, British Caucasian and Saudi populations as well as people native to Portugal, China, Kenya, the Sudan and the Philippines.

They found that some populations were significantly more likely than others to contain the mutation.

The groups of African descent – Ghanaian, Kenyan, African American and Sudanese – had the mutation significantly less frequently than the Caucasian/Asian populations.

Because lack of the mutation is associated with higher expression of PGP and thus higher drug resistance, these findings mean that physicians may soon have the necessary tools for individualizing therapy, especially for people of African heritage. Extreme interventions would not be necessary because an existing medication that chemically inhibits the PGP protein could be given to people found to overexpress PGP.

Many factors affect survival rates among cancer patients. "While I believe that the biggest reason some African-American cancer patients do not do as well as Caucasian patients is because of their access to care, this finding suggests that there is a little bit more to it," McLeod says. "Knowing this, we should be able to help decrease the variability in the way people are treated."

Previous studies have shown that there are ethnic and racial differences in the ability to make several proteins important for successful drug therapy. "So it’s always been an interest of mine not to confine my investigations to 18- to 35-year-old Caucasian males, which is where most drugs are studied, but to try to look at males and females of different ethnic groups," McLeod says.

Ameyaw M-M, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N, Folayan GO, Githang’a J, Indalo A, Ofori-Adjei D, Price-Evans DA, McLeod HL. MDR1 pharmacogenetics: Frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Presented at American Association for Cancer Research Annual Meeting March 24, 2001.

Funding from the Wellcome Trust supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.












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