Biochemical Basis for Fluorouracil Neurotoxicity: The Role of Krebs Cycle Inhibition by Fluoroacetate
TL;DR: F fluorouracil, like other agents which block DNA synthesis, is toxic chiefly to rapidly dividing normal cells, ie, epithelial cells of the alimentary tract and hematopoietic elements of bone marrow and lymphoid tissues.
Abstract: THE PYRIMIDINE analog fluorouracil has been used extensively in the chemotherapy of malignant neoplasms since its introduction by Heidelberger and associates in 1957. 1 The carcinostatic property of fluorouracil seems to be due to anabolic reactions. Although fluorouracil is readily converted to acid-soluble fluorouracil nucleotides, undergoes incorporation into RNA, and interferes with RNA synthesis in mammalian tissues and tumor cells, 2 its major chemotherapeutic and toxic effects are attributable to an interference with DNA synthesis and cell division. The latter effect is due to inhibition of thymidylate synthetase, the enzyme which catalyzes the conversion of deoxyuridylate of thymidylate, by the fluorouracil derivative fluorodeoxyuridylate (FUDR). 2 Thus fluorouracil, like other agents which block DNA synthesis, is toxic chiefly to rapidly dividing normal cells, ie, epithelial cells of the alimentary tract and hematopoietic elements of bone marrow and lymphoid tissues. 3-5 Recently, Riehl and Brown 6 described an acute neurological disorder
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TL;DR: A markedly prolonged elimination half-life was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FURA.
Abstract: Severe neurotoxicity due to 5-fluorouracil (FUra) has previously been described in a patient with familial pyrimidinemia. We now report the biochemical basis for both the pyrimidinemia and neurotoxicity in a patient we have recently studied. After administration of a "test" dose of FUra (25 mg/m2, 600 microCi[6-3H]FUra by intravenous bolus) to a patient who had previously developed neurotoxicity after FUra, a markedly prolonged elimination half-life (159 min) was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FUra. Using a sensitive assay for dihydropyrimidine dehydrogenase in peripheral blood mononuclear cells, we demonstrated complete deficiency of enzyme activity in the patient and partial deficiency of enzyme activity in her father and children consistent with an autosomal recessive pattern of inheritance. Patients who are deficient in this enzyme are likely to develop severe toxicity after FUra administration.
485 citations
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TL;DR: It is suggested that coadministration of oxonic acid suppresses the GI toxicity of 5-FU and its derivatives without affecting their antitumor activity and thus prolongs the life span of cancer-bearing rats.
Abstract: The possibility of decreasing the gastrointestinal (GI) toxic effects of 5-fluorouracil (5-FU) on the digestive tract such as its injury of cells and induction of diarrhea, without reducing its antitumor activity, was investigated in rats. Oxonic acid was found to inhibit the phosphorylation of 5-FU to 5-fluorouridine-5'-monophosphate catalyzed by pyrimidine phosphoribosyl-transferase in a different manner from allopurinol in cell-free extracts and intact cells in vitro. On p.o. administration of 5-FU (2 mg/kg) and a potent inhibitor of 5-FU degradation to Yoshida sarcoma-bearing rats, oxonic acid (10 mg/kg) was found to inhibit the formation of 5-fluorouridine-5'-monophosphate from 5-FU and its subsequent incorporation into the RNA fractions of small and large intestine but not of tumor and bone marrow tissues. This selective inhibition of 5-FU phosphorylation in the GI tract was due to the much higher concentrations of oxonic acid in GI tissues than in other tissues and the blood. On p.o. administration with the 5-FU derivative, UFT, which is a combined form of 1 M tegafur and 4 M uracil and usually administered p.o. to cancer patients in Japan, oxonic acid (10-50 mg/kg) markedly reduced injury of GI tissues and/or severe diarrhea without influencing the antitumor effect of UFT. These findings suggest that coadministration of oxonic acid suppresses the GI toxicity of 5-FU and its derivatives without affecting their antitumor activity and thus prolongs the life span of cancer-bearing rats.
348 citations
Cites background from "Biochemical Basis for Fluorouracil ..."
...bone marrow tissue (10), whereas its cardiotoxicity and neurotoxicity are induced by its catabolic products in the heart and brain (11)....
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TL;DR: 5-FU cardiotoxicity is an infrequent but real phenomenon that is independent of dose and may be related to a continuous infusion schedule and should be observed closely and 5-FU administration discontinued if cardiac symptoms develop.
Abstract: Background: The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined. Patients and methods: We performed a literature review (1969 – 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases. Results: Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were < 750 mg/m2/day (36%), 751 – 999 (16%), 1,000 (26%), 1,001 – 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone pr...
204 citations
Cites background from "Biochemical Basis for Fluorouracil ..."
...Only a few laboratory or animal studies have been done that contribute to our understanding of 5-FU’s effect on the heart or vascular endothelium [12,97]....
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TL;DR: (Second of Two Parts) Cytidine and Deoxycytidine Analogues The pyrimidine nucleoside analogues cytosine arabinoside (cytarabine) and 5-azacytidine are of importance in the treatment of acute granul...
Abstract: Cytidine and Deoxycytidine Analogues The pyrimidine nucleoside analogues cytosine arabinoside (cytarabine) and 5-azacytidine are of importance in the treatment of acute granulocytic leukemia. Altho...
202 citations
TL;DR: Recognizing the increasing use of 5‐FU, the authors tried to map this syndrome and observed a case of reversible cardiogenic shock linked to 5‐fluorouracil (5‐FU).
Abstract: Background. A case of reversible cardiogenic shock linked to 5-fluorouracil (5-FU) was observed. Recognizing the increasing use of 5-FU, the authors tried to map this syndrome.
Methods. They reviewed 134 additional case reports, retrieved information from literature searches, focused on clinical features, and discussed possible pathophysiologic findings and prevention of this syndrome.
Results. Although angina and electrocardiographic changes were common and reproducible (approximately 90% each), coronary artery disease was found in a few patients. A total of 33 patients had severe left ventricular dysfunction, 28 without evidence of myocardial infarction. The symptoms were responsive to conservative management (90%).
Conclusions. Cardiac toxicity is a little known complication of 5-FU therapy, with an unknown but significant incidence. It is highly treatable.
178 citations
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1,461 citations
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TL;DR: The activity of a new series of fluorinated pyrimidines has been screened against several transplanted tumors and the toxicity of 5-fluorouracil was characterized by delayed deaths, hematopoietic depression, diarrhea, weight loss, and hemorrhages in the lungs and intestines.
Abstract: 1. The activity of a new series of fluorinated pyrimidines has been screened against several transplanted tumors.
2. In general, the activity of 5-fluorouracil was greater than that of 5-fluoroorotic acid. 5-Fluorocytosine, 2-methylmercapto-5-fluorouracil, and 2-thio-5-fluorouracil did not have appreciable tumor-inhibitory activity.
3. The toxicity of 5-fluorouracil was characterized by delayed deaths, hematopoietic depression, diarrhea, weight loss, and hemorrhages in the lungs and intestines.
4. These compounds acted as tumor growthinhibitors rather than as carcinolytic substances.
5. The activity of 5-fluorouracil was considerably greater than that of 6-mercaptopurine and OPSPA on the Ehrlich ascites carcinoma, Novikoff hepatoma, and L1210 leukemia, and less than either or both of those compounds on Sarcoma 180, 755 and E 0771 mammary adenocarcinomas, Sarcoma A-1, Flexner-Jobling carcinoma, Walker 256 carcinosarcoma, and Yoshida ascites sarcoma.
6. Some potentiation of activity against the solid tumors has been obtained when 5-fluorouracil was combined with 6-mercaptopurine, 5-bromouracil, or x-ray treatment.
455 citations
TL;DR: Thiourea was chosen for study because of its solubility in water, ease of purification, and availability, and the development of a new colorimetric reaction with a higher extinction coefficient was of critical importance in studies.
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