New York, Feb 16 (IANS) Setting the stage to expand the use of a patient’s genetic make-up to tailor chemotherapy, an international research team has found how inherited gene variations lead to severe drug toxicity that may threaten chances for a cure in children with leukemia.
The research focused on treatment-related toxicity associated with a class of medication called thiopurines, which are widely used as anti-cancer and immunosuppressing drugs.
Thiopurines such as mercaptopurine are indispensable for curing acute lymphoblastic leukemia (ALL), the most common childhood cancer.
In the study involving 270 children with ALL, the scientists discovered four inherited variations in the NUDT15 gene that alter thiopurine metabolism and leave patients particularly sensitive to the drugs and at risk for treatment-disrupting toxicity.
One in three Japanese patients in this study carried the high-risk variations.
Evidence suggests that the variations are also common in other populations across Asia and those of Hispanic ethnicity, the researchers said.
“This study is key to the development of more effective, personalised ALL therapy because it provides a clear explanation of how variations in the NUDT15 gene change drug metabolism and cause toxicity in patients,” said lead researcher Jun Yang from St. Jude Children’s Research Hospital in Tennessee, US.
In the study published in the journal Nature Genetics, the researchers demonstrated that the NUDT15 enzyme helps to balance thiopurine activity by reducing the supply of the active drug metabolite that triggers cell death.
This check-and-balance mechanism helps to prevent the excessive death of white blood cells that put patients at high risk for infections and other serious complications.
The scientists showed the high-risk NUDT15 variants cause a 74.4 to 100 percent loss of NUDT15 function and a toxic build-up of the drug at standard doses.
“We are planning clinical studies to move these findings from the laboratory to the clinic with the hope to guide individualised therapy in the future,” Yang said.