Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency: a potentially more common pharmacogenetic syndrome

Article Abstract:

In some cases, breast cancer patients receive adjuvant chemotherapy after surgical removal of their cancer. The rationale is to destroy any microscopic deposits of cancer cells that may be outside the primary area removed during surgery. In a recent case, a 35-year-old woman, developed severe toxic effects in response to the adjuvant chemotherapy that consisted of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU). The patient developed severe gastrointestinal symptoms including stomatitis and diarrhea as well as mild neurologic symptoms including difficulties with balance and spelling simple words. The patient had abnormally low levels of white blood cells. The toxic reaction was found to be the result of a genetic defect that made this patient susceptible to toxic effects of 5-FU, even at normal doses. The patient was found to have a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD); further evaluation revealed that both her mother and father carried a single defective gene for this enzyme. The case illustrates how an unsuspected genetic trait may affect the response to a drug. The drug 5-FU is a pyrimidine analog. It is similar in chemical structure to pyrimidines, such as thymine and cytosine, which are normally converted into substances called nucleotides in preparation for incorporation into DNA structure. When 5-FU is administered to a patient, less than 20 percent is metabolically converted into analogous, but toxic, nucleotides. The remainder is metabolically destroyed by DPD. Therefore, a deficiency of DPD results in a much higher amount of toxic 5-FU by-products. In the present case, the removal of 5-FU from the chemotherapeutic regimen solved the problem, and the patient is now healthy and free of signs of cancer. Since severe toxic reactions may result from an enzyme deficiency, patients showing such reactions should be tested for enzyme activities. Unrecognized DPD deficiency may be more common than previously suspected. (Consumer Summary produced by Reliance Medical Information, Inc.)

Complications and side effects, Genetic aspects, Enzymes

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The Duke AFM program: intensive induction chemotherapy for metastatic breast cancer

Article Abstract:

Metastatic breast cancer is a malignancy of the breast tissue associated with the spreading of cancer cells to other body sites. Because this disease is not considered curable, most treatment methods are designed only to reduce symptoms and disease severity. An intensive dose schedule of the anticancer agent doxorubicin produced complete remission for longer than 18 months in only three of 26 patients treated and caused toxic effects on the heart. Treatment with the anticancer agents cyclophosphamide, cisplatin, and carmustine with bone marrow support to maintain marrow function produced complete remission in 15 percent of patients for longer than 18 months. Because relapses occurred in tissues with a large amount of tumor, it was suggested that a reduction in tumor size may improve responses to treatment. The effectiveness of the combined use of these treatment approaches was assessed in 45 patients with metastatic breast cancer. The drug regimen consisted of doxorubicin, 5-fluorouracil, methotrexate, and a method to maintain bone marrow function called 'folinic acid (or leucovorin) rescue' (AFM), and was designed to shrink the tumor rapidly and extensively before treating patients with high doses of alkylating-type anticancer agents and bone marrow support. Ninety-one percent of the patients responded to treatment, and complete clinical response was achieved in 38 percent after an average of 70 days of treatment. These findings show that AFM is effective in producing remission in patients with metastatic breast cancer. However, the considerable toxicity of the regimen must be considered in its routine use for breast cancer. (Consumer Summary produced by Reliance Medical Information, Inc.)

Breast cancer, Chemotherapy, Methotrexate, Doxorubicin

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