Abstract
We investigated the influence of recombinant human tumour necrosis factor alpha (TNF-α) and its derivatives termed muteins III, V, VI—in which the first 3 to 7 amino acids of native TNF-α have been replaced—on the survival time of mice inoculated with leukaemia L1210 or leukaemia P338. TNF-α prolonged the survival of mice with leukaemia L1210 but did not have any therapeutic activity in leukaemia P388-bearing mice. Muteins-treated mice with leukaemia P388 lived longer than animals receiving TNF-α, while those inoculated with leukaemia L1210 did not show any significant prolongation of life compared with the TNF-α treated group. The results presented in this report indicate that the antileukaemic activity of TNF-α is governed at least in part by the nature of the N-terminal amino acids.
Highlights
The multifunctional cytokine tumour necrosis factor-{x (TNF-(x) plays a role in the regulation of many biological responses in vivo, and has been implicated in a wide range of pathological conditions, including the host response to leukaemia growth. 1-5 As for cytokines in general, the first event in triggering a cellular response is a specific high affinity interaction with membrane receptor molecules initiating a cascade of signal transfer reactions inside the cell
Experiments performed with derivatives of TNF-( termed muteins, in which the first 3 to 7 amino acids of native TNF-(x have been replaced, indicate that the receptor-binding domain of TNF-(x may be located near the N-terminus of the molecule.[6,7]
Different treatment regimes with TNF-0t or its muteins III, V, VI against the two types of murine leukaemias were studied to compare their antitumour activities
Summary
The multifunctional cytokine tumour necrosis factor-{x (TNF-(x) plays a role in the regulation of many biological responses in vivo, and has been implicated in a wide range of pathological conditions, including the host response to leukaemia growth. 1-5 As for cytokines in general, the first event in triggering a cellular response is a specific high affinity interaction with membrane receptor molecules initiating a cascade of signal transfer reactions inside the cell. 1-5 As for cytokines in general, the first event in triggering a cellular response is a specific high affinity interaction with membrane receptor molecules initiating a cascade of signal transfer reactions inside the cell. Two cell surface receptors for TNF-et have been identified, the amino acid residues necessary for the biological activity of TNF-0t have not been characterized. Experiments performed with derivatives of TNF-( termed muteins, in which the first 3 to 7 amino acids of native TNF-(x have been replaced, indicate that the receptor-binding domain of TNF-(x may be located near the N-terminus of the molecule.[6,7] In the present study we compare the antitumour effects of TNF-(x and its N-terminal region muteins in murine leukaemia model
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