Diatech Pharmacogenetics is pleased to announce the release of new kit “Fluoropyrimidines Response®” (cod. UP024), updated to detect the polymorphism 2846A> T into the DPYD gene

The fluoropyrimidine chemotherapy are widely used for the treatment of various solid tumors, including tumors of the colon-rectum, and breast.

These drugs have a narrow therapeutic index and are frequently associated with adverse reactions of high level that may require discontinuation of treatment. A fraction of about 10-40% of patients treated with 5-fluorouracil develops high, and sometimes even fatal, hematologic toxicity, gastrointestinal or neurological.

Only 1-3% of the administered dose of 5-fluorouracil is converted to cytotoxic metabolites, while about 80% is rapidly degraded. The enzyme dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the main catabolizzatore of 5-florouracile presents and activity levels vary widely in the population.

Reduced or absent activity of the enzyme DPD is correlated with a high risk of developing toxic effects following treatment with fluoropyrimidine.

Several polymorphisms of the DPYD gene have been identified which can lead to reduced or absent activity of the enzyme DPD. In particular, several studies have shown a correlation between polymorphisms in DPYD*2A (DPYD IVS14 + 1G> A, rs3918290) and DYPD 2846A> T (rs67376798) and the development of a highly lethal toxicity. In detail, patients heterozygous for these polymorphisms show partial activity of the enzyme DPD, while individuals homozygous mutant showed a deficiency in the activity of DPD.

Therefore, in patients who are carriers of these variants is recommended a reduction in the dose of fluoropyrimidines, while in the homozygous mutant assessment of alternative drugs appears necessary to prevent the occurrence of toxic effects of high level even life-threatening.

Consequently, the evaluation of the mutational status of DPYD gene in patients eligible for treatment with fluoropyrimidine has an important role in the planning of therapy in view, especially, the reduction in the risk of onset of severe adverse effects.

The kit “FLUOROPYRIMIDINES Response®” cod.UP024 allows to identify, using Pyrosequencing, in addition to polymorphisms DPYD IVS14 +1 G> A (rs3918290) and DPYD 2846A> T (rs67376798) also variants TSER 28bp VNTR (rs45445694), MTHFR C677T (rs1801133) and A1298C MTHFR (rs1801131), which also influence the outcome of chemotherapy with fluoropyrimidines.

Bibliography
Amstutz U, Froehlich TK, Largiadèr CR. Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics 2011, 12 (9), 1321-1336.
CPIC. Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clinical Pharmacology & Therapeutics vol.94 Ranked # 6 December 2013.
Lee A et al. Validation of DPYD * 2A, I560S, D949V as predictors of 5-fluorouracil (5FU) -related toxicity in Stage III colon cancer (CC) patients from adjuvant trial NCCTG N0147. J. Clinical Oncology 2013 31, suppl. abstr 3501.
Del Re M et al. Impact of IVS14 + 1G> A and 2846A> T DPYD polymorphisms on toxicity outcome of patiens treated with fluoropyrimidine-containing regimens. J. Clinical Oncology 2013 31, suppl. abstr 11058.
Deenen MJ, Tol J, Burylo AM et al. Relationship between Single Nucleotide Polymorphisms and Haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clinical Cancer Research 17 (10) May 15, 2011.

2017-08-28T12:20:13+00:00