Variations in 2 genes, DPYD and TYMS, are responsible for a significant portion of serious adverse reactions to 5-FU–based therapy1-4
Effects of DPD and TS on 5-FU–related therapy
Functional interaction of DPD and TS genetic variants
Clinical doses of 5-FU are normally metabolized by DPD enzyme, such that approximately 15% of dosed 5-FU remains. Genetic variants of DPD reduce 5-FU metabolism to varying degrees, resulting in dramatic increases in effective 5-FU dose available to inhibit its target, thymidylate synthetase (TS).
Genetic variation in the gene encoding TS has a significant effect on the amount of TS enzyme present. TS is essential for DNA replication in tumor and normal cells. Combinations of DPD and TS variants may potentially have extreme effects on toxicity. For example, DPD variants causing complete DPD deficiency, combined with a 2R/2R TS genotype (lower enzyme expression) would likely cause overwhelming inhibition of TS in both tumor and normal tissue, possibly resulting in extreme toxicity. A normal DPD genotype combined with large amounts of TS enzyme associated with other TS genotypes theoretically could result in suboptimal TS inhibition or therapeutic effect.
- 1 in 4 individuals carries variations in either the DPYD or TYMS genes that will increase their risk of dose-limiting toxicity. These variations confer up to a 60% risk of toxicity to 5-FU–related therapies.
"...given the large number of patients treated each year with 5-FU...and the human and economical cost of grade 3 and 4 toxic side effects, pretherapeutic detection of DPD deficiency should be considered." 1
Reference: 1. Morel A, Boisdron-Celle M, Fey L, et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther. 2006;5:2895-2904.
