A common feature of many advanced cancers is their enhanced capacity to metabolize glucose to lactic acid. In a challenging study designed to assess whether such cancers can be debilitated, we seeded hepatocellular carcinoma cells expressing the highly glycolytic phenotype into two different locations of young rats. Advanced cancers (2-3 cm) developed and were treated with the alkylating agent 3-bromopyruvate, a lactate/pyruvate analog shown here to selectively deplete ATP and induce cell death. In all 19 treated animals advanced cancers were eradicated without apparent toxicity or recurrence. These findings attest to the feasibility of completely destroying advanced, highly glycolytic cancers. (C) 2004 Elsevier Inc. All rights reserved.