Regression of hepatocellular cancer in a patient treated with arginine deiminase

We report the first pharmacokinetic and clinical response data from a patient with unresectable hepatocellular cancer treated with a new drug, ADI-PEG_{20,000 mw} (arginine deiminase-polyethylene glycol 20,000 molecular weight). A single patient with idiopathic cirrhosis and unresectable hepatocellular cancer was treated with escalating dosages of ADI-PEG_{20,000 mw}. Human hepatocellular cancer has been found to be arginine-dependent for growth because of loss of expression or arginosuccinate synthetase, the rate-limiting enzyme in the conversion of citrulline to arginine. Thus, an arginine-degrading enzyme like ADI-PEG_{20,000 mw} should produce cell death in hepatocellular cancer cells without significantly affecting normal cells. There was a dose-dependent reduction of plasma arginine levels after weekly intramuscular administration of ADI-PEG_{20,000 mw}. Successive treatment cycles at the optimal biologic dose of 160 IU/m² led to reduction in tumor size and serum alpha-fetoprotein levels. Sufficient tumor cytoreduction was achieved with ADI-PEG_{20,000 mw} treatment to permit surgical treatment. The patient developed no toxicities or side effects related to ADI-PEG_{20,000 mw} treatment. The results in a single patient with unresectable hepatocellular cancer treated with ADI-PEG_{20,000 mw} suggests this may be a promising, low-toxicity treatment. Full-scale clinical trials have been initiated.