Genetics may play a role in the effectiveness of chemotherapy drugs

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Today, the most common childhood cancer is cured in about 80 percent of patients; only forty years ago, this number was closer to five percent. In efforts to further increase the survival rate, researchers from St. Jude Children's Research Hospital, the University of Tennessee, and the University of Chicago studied how an individual's genetics might play a role in the effectiveness of chemotherapy drugs.

Their findings will be published in the June 15, 2005, issue of Blood, the official journal of the American Society of Hematology.

The researchers studied 246 children with acute lymphoblastic leukemia (ALL), all of whom were assigned to one of two groups that determined the intensity of therapy. Patients with poorer prognostic factors – 130 children – were assigned to a high-risk group; the remaining children were enrolled in the lower-risk arm.

In a process known as genotyping, DNA was extracted from the normal blood cells of each child and screened for sixteen common genetic variations. The studied genes code for enzymes which are involved in the metabolism and activity of chemotherapy drugs in the body, and were therefore likely to have effects on treatment outcomes.

In the analysis of the high-risk group, the GSTM1 non-null genotype was associated with hematological relapse, a recurrence of the cancer in the blood and bone marrow and the most common reason for treatment failure in childhood ALL. This risk was further increased if the child also had a TYMS 3/3 genotype. No genotype was associated with hematological relapse among patients in the lower-risk arm of the study.

The researchers also looked for evidence of leukemia in each patient's central nervous system (CNS), a region that is vulnerable to infiltration by cancer cells. Genetic variations may have particular impact on how drugs penetrate the "blood-brain" barrier that protects the CNS. For patients in the high-risk arm, the VDR FokI genotype was found to be prognostic for CNS relapse, especially when combined with a VDR intron 8 genotype. In the low-risk group, the TYMS 3/3 genotype was a risk factor.

For children with these unfavorable genotypes, a potential solution may be using drugs that are not affected by these particular enzymes or increasing the dosage of drugs that are. And, in the future, a simple blood test may be all that's needed to make that determination.

"This research showcases a new direction for cancer treatment – personalized chemotherapy based on the genetics of the patient," said Mary Relling, Pharm.D., St. Jude faculty member and lead study author. "In our study, several common genetic variations were found to predict the outcomes of leukemia patients, demonstrating that genotyping may become an important tool for tailoring treatment and improving an individual's chance of a cure."

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