5- fluorouracil toxicity ...; Dihydropyrimidinase deficiency; Dihydropyrimidine dehydrogenase deficiency (Dihydropyrimidinase deficiency; dihydropyrimidine dehydrogenase deficiency) - Genes and DPYD DPYS.

5-fluorouracil (5-FU) is one of the most chemotherapeutic agents used for treatment of gynecologic tumors, adenocarcinomas of gastrointestinal, breast, prostate, head and neck cancer. The mode of action of 5-FU is inhibition by irreversible binding, of thymidylate synthase, which is an essential enzyme for the synthesis of thymine nucleotides. Thus, the synthesis of thymine is prevented and thus, DNA replication, inhibiting cell division and therefore tumor growth.

Toxicity 5- fluorouracil may be due to alterations in DPYS and DPYD gene. Changes in these genes result in a deficiency of dihydropyrimidinase and dehydrogenase, respectively dihydropyrimidine. People deficient dihydropyrimidinase and dihydropyrimidine dehydrogenase, may be vulnerable to severe and potentially fatal toxic reactions to certain drugs called fluoropyrimidines used to treat cancer, including 5-fluorouracil and capecitabine. These drugs can not be decomposed effectively and may accumulate to toxic levels in the body, leading to drug reactions, gastrointestinal problems, blood disorders, and other signs and symptoms. Specifically, fluoropyrimidines toxicity can cause intense inflammation and ulceration of the mucosa of the gastrointestinal tract, which can lead to signs and symptoms including mouth sores, abdominal pain, bleeding, nausea, vomiting and diarrhea. In addition, toxicity to these drugs can also cause neutropenia, with the risk of infections and thrombocytopenia, which affects blood clotting and may be cause of bleeding. Other signs and symptoms may include redness, swelling, numbness and peeling skin on the palms of hands and soles of the feet, difficulty breathing and loss of hair.

In addition, vulnerability to toxic reactions against fluoropyrimidine, individuals deficient dihydropyrimidinase and dihydropyrimidine dehydrogenase may have neurological and gastrointestinal problems. Neurologic abnormalities that occur most often include mental retardation, seizures and hypotonia or hypertonia. In addition, affected individuals may have microcephaly and autistic behaviors that affect communication and social interaction. Meanwhile, gastrointestinal problems associated include gastroesophageal reflux and cyclic vomiting. Similarly, these individuals may have atrophy of the villi lining the small intestine, which can lead to difficulty absorbing nutrients from food and therefore to growth retardation.

The DPYS gene, located on the long arm of chromosome 8 (8q22), encoding dihydropyrimidinase enzyme involved in the degradation of pyrimidines, basic components of DNA and RNA. Specifically, dihydropyrimidinase enzyme is involved in the second of the three stage process of metabolization of pyrimidines. This step opens the ring - shaped structures of molecules dihydrothymine 5.6 and 5.6 dihydrouracil so they can be degraded. In addition, the dihydropyrimidinase enzyme also helps break down fluoropyrimidine used to treat cancer. They have identified at least 23 mutations in the gene in people DPYS deficient dihydropyrimidinase. These genetic changes reduce or eliminate the function of the enzyme dihydropyrimidinase. As a result, the enzyme is unable to initiate the decomposition of dihydrouracil and dihydrothymine 5.6 5.6, so that excessive amounts of these molecules in blood and cerebrospinal fluid build up and released into the urine. The relationship between the inability to break dihydrothymine dihydrouracil 5.6 and 5.6 and the specific characteristics of the disease is unclear. A reduced production of these molecules can alter its function in the nervous system, leading to neurological problems in some people deficient dihydropyrimidinase. Furthermore, because the fluoropyrimidine drugs are broken down by the same three - stage process that pyrimidines deficiency dihydropyrimidinase enzyme can lead to a toxic buildup of fluoropyrimidines. However, it is unknown why some people with dihydropyrimidinase deficiency do not develop health problems related to the disease. Other genetic and environmental factors likely to help determine the effects of this disease.

Meanwhile, the DPYD gene, located on the short arm of chromosome 1 (1p22), encodes the enzyme dihydropyrimidine dehydrogenase, which is involved in the degradation of uracil and thymine molecules. Specifically, dihydropyrimidine dehydrogenase is involved in the first step in the degradation of pyrimidines. This enzyme converts 5,6-dihydrouracil uracil and thymine to 5,6-dihydrothymine. Molecules are created when break down pyrimidines are excreted by the body or used in other cellular processes. There are more than 50 mutations in the gene DPYD in people with dihydropyrimidine dehydrogenase deficiency. These mutations result in a functional dihydropyrimidine dehydrogenase deficiency. As a result, the degradation of uracil and thymine is altered, which causes an excess of these molecules in blood, urine and cerebrospinal fluid. It is unclear how excess uracil and thymine are related to signs and symptoms of specific dihydropyrimidine dehydrogenase deficiency. Since the fluoropyrimidine is also degraded by the enzyme dihydropyrimidine dehydrogenase, this enzyme deficiency leads to the accumulation of the drug which causes toxicity.

The detection of mutations in genes DPYD DPYS and allows identification of patients at risk and the search for alternative cancer treatments to 5-FU, thereby avoiding the risks associated with this drug in the relevant individuals. The recommended strategy would start the study prior to drug administration way to avoid as far as possible the risk of severe toxicity associated with 5-FU.

Dihydropyrimidinase deficiency and dihydropyrimidine dehydrogenase, and therefore toxicity to 5-fluorouracil, are inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with deficiency dihydropyrimidinase and dihydropyrimidine dehydrogenase deficiency, by complete PCR amplification of the exons of DPYS and DPYD, respectively, genes and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).