The Dihydropyrimidine Dehydrogenase Deficiency Laboratory of Robert B. Diasio, M.D., at Mayo Clinic is interested in identifying interindividual differences in drug metabolism, which can serve to both activate and inactivate drugs, and drug uptake and excretion, which contribute to variability in response and toxicity to various chemotherapeutics.
Drug-related adverse toxicity is one of the most significant barriers preventing the delivery of chemotherapy doses that are effective against cancer.
The Dihydropyrimidine Dehydrogenase Deficiency Lab takes a multifaceted approach to understanding this complex problem using a broad array of model systems and clinical specimens to investigate genetic, epigenetic and biochemical pathways of drug toxicity and resistance.
Dr. Diasio's laboratory was instrumental in identifying the dihydropyrimidine dehydrogenase (DPD) enzyme as a critical determinant of adverse toxicity to the commonly used chemotherapy drug 5-fluorouracil (5-FU). DPD rapidly inactivates approximately 85 percent of 5-FU in the liver within minutes of drug administration.
Members of Dr. Diasio's laboratory team recently undertook a comprehensive study of genetic variants in the gene encoding DPD for their effect on 5-FU inactivation using a combination of in vitro, cellular and clinical studies. The Dihydropyrimidine Dehydrogenase Deficiency Lab also identified and characterized clinically relevant mechanisms by which DPD expression is controlled.
Dr. Diasio's laboratory is now expanding these methodologies to evaluate pharmacological pathways relevant to additional chemotherapies.
The Dihydropyrimidine Dehydrogenase Deficiency Lab expects that these studies will make possible precision medicine-based approaches to individualize anti-cancer treatments to maximize drug efficacy while minimizing adverse toxicity.