The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma.

摘要: Argininosuccinate synthetase (ASS), a key enzyme to synthesize arginine is down regulated in many tumors including hepatocellular carcinoma (HCC). Similar previous reports, we have found the decrease ASS expression poorly differentiated HCC. These ASS(-) are auxotrophic for arginine. Pegylated deiminase (ADI-PEG20), which degrades arginine, has shown activity these tumors, but antitumor effect not robust and hence combination treatment needed. Herein, elucidated effectiveness of ADI-PEG20 combined with 5-Fluorouracil (5-FU) ASS(-)HCC by targeting urea cycle pyrimidine metabolism using four HCC cell lines as model. SNU398 SNU387 express very low levels or while Huh-1, HepG2 high similar normal cells. Our results showed that augmented cytotoxic only occurs SNU387, Huh-1 (ASS(+)) cells, partly due reduced anti-apoptotic proteins X-linked inhibitor apoptosis protein (XIAP), myeloid leukemia differentiation (Mcl-1) B-cell lymphoma-2 (Bcl-2). Importantly, lack also influences essential enzymes synthesis (carbamoyl-phosphate synthetase2, aspartate transcarbamylase dihydrooratase (CAD) thymidylate synthase (TS)) malate dehydrogenase-1 (MDH-1) TCA cycle. decreased made them more vulnerable 5-FU. Transfection restored abolished sensitivity treatment. Overall, our data suggest multiple involved 5-FU sensitivity. Combining may be effective treat ASS(-)hepatoma warrants further clinical investigation.