title: 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.
authors.affiliation: Departamento de Fisiología, Universidad de Valencia, Facultad de Medicina, Av. Blasco Ibañez 17, 46010 Valencia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Obrador
authors.forename: J
authors.initials: J
authors.lastname: Navarro
authors.forename: J
authors.initials: J
authors.lastname: Mompo
authors.forename: M
authors.initials: M
authors.lastname: Asensi
authors.forename: J A
authors.initials: JA
authors.lastname: Pellicer
authors.forename: J M
authors.initials: JM
authors.lastname: Estrela
mesh_terms: D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019328:Buthionine Sulfoximine; C058293:glutathione monoisopropyl ester; D005978:Glutathione