Low rates of cellular proliferation are associated with low GSH content and enhanced sensitivity of Ehrlich ascites-tumour (EAT) cells to the cytotoxic effects of recombinant human tumour necrosis factor (rhTNF-α). Buthionine sulphoximine, a selective inhibitor of GSH synthesis, inhibited tumour growth and increased rhTNF-α cytoxicityin vitro. Administration of sublethal doses (106 units/kg per day) of rhTNF-α to EAT-bearing mice promoted oxidative stress (as measured by increases in intracellular peroxide levels, O2-• generation and mitochondrial GSSG) and resulted in a slight reduction (19%) in tumour cell number when controls showed the highest rate of cellular proliferation. ATP (1 mmol/kg per day)-induced selective GSH depletion, when combined with rhTNF-α administration, afforded a 61% inhibition of tumour growth and resulted in a significant extension of host survival. Administration of N-acetylcysteine (1 mmol/kg per day) or GSH ester (5 mmol/kg per day) abolished the rhTNF-α- and ATP-induced effects on tumour growth by maintaining high GSH levels in the cancer cells. Our results demonstrate that the sensitivity of tumour cells to rhTNF-αin vivo depends on their GSH content and their rate of proliferation.
- The Biochemical Society, London © 1997