Treatment of HCC cells with ADI-PEG20 downregulates the key enzymes of pyrimidine synthesis in the TCA cycle, carbamoyl phosphate synthetase 2, thymine synthase (TS), aspartate transcarbamylase and dihydrooratase (CAD) and malate dehydrogenase 1 (MDH-1) activities, making tumor cells more susceptible to 5-fluorouracil (5-FU). The gene discussed is MDH1; the disease is hepatocellular carcinoma.