Genetic Polymorphisms Associated with 5-Fluorouracil-Induced Neurotoxicity

Abstract

Background: Encephalopathy is a rare drug toxicity of fluorouracil therapy. Toxicity from fluorouracil therapy is known to be associated with the individual genetic background of the enzymes, thymidylate synthase and dihydropyrimidine dehydrogenase. Methods: Two patients with advanced gastric cancer and metastatic pancreatic cancer who received 5-fluorouracil-based chemotherapy presented with acute mental change and hyperammonemia. To evaluate the genetic background of the fluorouracil-associated hyperammonemic encephalopathy, analysis of the polymorphisms of the TYMS, DPYD and MTHFR genes was performed. Results: The patients revealed to be TYMS suppressors showing homogenous deletion of 6 bp in the 3′-UTR and 3RC/3RC genotype in the promoter enhancer region (TSER), respectively. Conclusion: Genetic polymorphisms of the TYMS gene would contribute to the 5-fluorouracil-associated hyperammonemic encephalopathy. The prospective validation of the clinical implication of TYMS gene polymorphisms is warranted.

Gastric Antral Vascular Ectasia (GAVE): An Update on Clinical Presentation, Pathophysiology and Treatment

“…Cirrhosis of the liver is found in 30% of GAVE patients [10]. Data obtained from screening gastroscopies on patients undergoing liver transplantation suggest that 1 in 40 patients with endstage liver disease has GAVE [10]. …”

“…A report of 3 patients showing a complete resolution of GAVE following liver transplantation suggests, again, a causal link [10]. Further support for this theory is provided by the fact that GAVE patients tend to have higher degrees of liver dysfunction than patients with portal hypertensive gastropathy [6].…”

5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases

“…Beside haematological toxicities, some drug-induced neurotoxicities have been described with 5-FU, although this latter are by far less frequent and usually are not dose limiting [6]. It has been recently suggested that such neurotoxicities could be associated with deregulation in TYMS, another pharmacogenomic syndrome linked with outburst of severe toxicities with 5-FU [7]. To date, little relationships have been evidenced between DPD deficiency and increased risk of developing neurotoxicity in patients undergoing 5-FU treatment [8].…”

5-Fluorouracil Induced Hyperammonemic Encephalophathy: Etiopathologic Correlation

“…High glutamine levels in astrocytes raise intracellular osmolality and result in astrocyte swelling and cerebral edema. Some authors have reported that genetic polymorphisms of the thymidylate synthetase gene could contribute to the 5fu induced He 4 . Moreover, as late-onset urea cycle deficiencies have been diagnosed in adults under stress situations or metabolic insults, a genetic mutation of these enzymes should be considered.…”