Molecular Diagnostic Test Helps Avoid Chemotherapy-Related Toxicity

A new molecular diagnostic test will help predict which cancer patients are likely to suffer serious toxic reactions to the drug 5-fluorouracil (5-FU) or the oral form of the drug, capecitabine.

The test, TheraGuide 5-FU, is a comprehensive analysis of the genetic variations in two genes, dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS), which increase a patient's risk for toxicity to 5-FU chemotherapy. With the test results, oncologists and their patients can take steps to reduce the risk of avoidable toxicity, including using alternative therapies, reducing the size of the dose, and increasing patient monitoring for side effects. TheraGuide 5-FU provides the critical guidance oncologists need to personalize chemotherapy for their cancer patients who are being considered for chemotherapy regimens.

Approximately one-third of all patients treated with 5-FU experience dose-limiting toxicity that can be severe to life threatening. The majority of these toxic reactions are due to genetic variations in the DPYD and TYMS genes. The DPYD gene makes the enzyme dihydropyrimidine dehydrogenase, which is primarily responsible for metabolizing or breaking down 5-FU and clearing it from the body quickly. If the DPYD enzyme activity is compromised, 5-FU will be cleared more slowly from the system resulting in a longer period of exposure to 5-FU. An estimated nine million individuals in the United States have low DPYD enzyme activity due to mutations in the DPYD gene.

Thymidylate synthase is an essential enzyme for DNA synthesis. The chemotherapy drug 5-FU binds to the TYMS enzyme, inhibiting its function. When the TYMS enzyme is inhibited, DNA stops being synthesized and the cell dies. Since cancer cells multiply rapidly and require a high level of DNA synthesis, they are much more sensitive to thymidine depletion than normal cells. The human TYMS gene has genetic variations that cause differential production of the TYMS enzyme. If a variation causes underproduction of TYMS, only a portion of the 5-FU dose can bind to, and inhibit, the TYMS enzyme; the rest remains unbound in the body resulting in increased toxicity. Variations causing overproduction of TYMS enzyme lead to excess TYMS, and thus there is insufficient 5-FU to completely inhibit the enzyme. This results in loss of efficacy of the 5-FU chemotherapeutic agent.

Toxicity reactions due to reduced enzyme activity include hand-foot syndrome, fever, mucositis, stomatitis, and severe diarrhea. Nausea, vomiting, rectal bleeding, and skin changes may also occur. Neurologic abnormalities include cerebellar changes, ataxia (uncoordinated muscle movement), and alterations in cognitive ability. Elimination of 5-FU from the treatment regimen is usually sufficient to prevent additional unexpected toxicities.

Developed by Myriad Genetics, Inc. (Salt Lake City, UT, USA), TheraGuide 5-FU is the company's fifth molecular diagnostic product. The company focuses on the development and marketing of novel therapeutic and molecular diagnostic products.


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