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Glutathione and the rate of cellular proliferation determine tumour cell sensitivity to tumour necrosis factor in vivo.

ABSTRACT: 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-alpha). Buthionine sulphoximine, a selective inhibitor of GSH synthesis, inhibited tumour growth and increased rhTNF-alpha cytoxicity in vitro. Administration of sublethal doses (10(6)units/kg per day) of rhTNF-alpha 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 (1mmol/kg per day)-induced selective GSH depletion, when combined with rhTNF-alpha administration, afforded a 61% inhibition of tumour growth and resulted in a significant extension of host survival. Administration of N-acetylcysteine (1mmol/kg per day) or GSH ester (5mmol/kg per day) abolished the rhTNF-alpha- 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-alpha in vivo depends on their GSH content and their rate of proliferation.

SUBMITTER: Obrador E

PROVIDER: S-EPMC1218544 | biostudies-other | 1997 Jul

REPOSITORIES: biostudies-other

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Depletion of tumour glutathione in vivo by buthionine sulphoximine: modulation by the rate of cellular proliferation and inhibition of cancer growth.

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Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells.

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