Brief description:

Some cancer patients do not tolerate treatment with 5-FU. This is because following administration 5-FU is rapidly metabolised by the liver enzyme DPD and removed from the blood. Individuals who lack this enzyme are at risk of severe and sometimes life threatening toxicity. Lack of the DPD enzyme also results defective metabolism of the endogenous compounds uracil and thymine. These compounds can be used to probe for enzyme activity and may predict the activity of this enzyme in patients prior to taking the chemotherapy Inherited variation in the DPYD gene can account for this toxicity in less than <30% of the affected patients. The underlying cause of this adverse event in the majority of people is still not known. Our colleagues in Australia found that patients who had previously experienced severe 5-FU toxicity had an abnormally rapid uptake of thymine after a test dose. This suggests that 5-FU toxicity may be due to aberrantly high cellular uptake in some individuals.

The aim of this research is to establish the ability of this thymine test to accurately detect aberrant disposition of 5-FU in NZ cancer patients and determine its usefulness to predict which individuals may be at risk of life-threatening 5-FU toxicity. Samples will also be collected from patients to provide a biobank resource for elucidation of variation in candidate genes.  Future development of this type of screening test may allow clinicians to determine which patients can and cannot tolerate treatment with 5-FU and improve the safety use of this drug.

Helsby NA, Duley J, Burns KE, Bonnet C, Jeong SH, Brenman E, Barlow P, Sharples K, Porter D, Findlay M.  A case-control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine-induced gastrointestinal toxicity. British Journal of Clinical Pharmacology. 2019;1-10. https://doi.org/10.1111/bcp.14153; 

Jeong SH, Chavani O, Burns K, Porter D, Findlay M, Helsby N. Severe 5‑fluorouracil‑associated gastrointestinal toxicity unexplained by dihydropyrimidine dehydrogenase deficiency and renal impairment: Should we be investigating other elimination pathways to assess the risk of 5‑fluorouracil toxicity? European Journal of Drug Metabolism and Pharmacokinetics. 2021; 46, 817-820 https://doi.org/10.1007/s13318-021-00721-0