Lynch, Eileen M.; (1996) The effect of oxygen tension on the cytotoxic action of tumour necrosis factor-alpha. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The influence of tumour relevant oxygen tensions on the cytotoxic action of TNFα on tumour cells, both in vitro and in vivo, was investigated. Tumour oxygen tensions were assessed in two murine tumours (SaF and CaNT), directly, using the Eppendorf pO2 histograph, and indirectly, by determining the radiobiological hypoxic fraction. These tumours are largely hypoxic with median pO2 values less than 2% oxygen (15 mmHg). Such oxygen tensions re-established in vitro induce resistance to TNFα cytotoxicity in murine and human tumour cell lines. The mechanism(s) of hypoxia-induced resistance to TNFα cytotoxicity was studied using the SaF cell line. The role of cell cycle was assessed but was found to be negligible. Western blotting and ELISA techniques were used to assess putative protective proteins such as manganese superoxide dismutase (MnSOD) and TNFα itself. MnSOD is not implicated in hypoxia-induced TNF-resistance. Endogenous TNFα levels were assessed and found to be significantly induced during hypoxic preincubation. Indeed, both pre-treatment of oxic cells with exogenous TNFα and overexpression of endogenous TNFα, by gene transfection, induced resistance to TNFα challenge. A growth delay assay and an in vivo/in vitro clonogenic assay determined that the direct cytotoxic action of TNFα in vivo is not the only mechanism implicated in its antitumour activity. Indeed, TNFα significantly reduces tumour blood flow, as demonstrated by laser Doppler flowmetry, and this may be largely responsible for the antitumour action of TNFα in vivo. The cytotoxic action of TNFα is dramatically modulated by oxygen tensions known to exist in tumours. Thus, overcoming tumour hypoxia could potentially increase TNFα cytotoxicity and together with the effective anti-vascular effects could perhaps improve the antitumour efficacy of TNFα.

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