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Lectin-deficient TNF mutants display comparable anti-tumour but reduced pro-metastatic potential as compared to the wild-type molecule

Authors
Lucas, Rudolf
Hafner, Michael
Sablon, Erwin
Grau, Georges E.
De Baetselier, Patrick
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Published in International Journal of Cancer. 2001, vol. 91, no. 4, p. 543-9
Abstract In this study, we characterised the anti-tumour as well as the pro-metastatic activities of TNF mutants deficient in their lectin-like activity.1619 We report that, despite reduced systemic toxicity as compared to wild-type (wt) mTNF, a (T104A) and a (T104A-E106A-E109A) mTNF mutant (triple mTNF) retained most of their necrotic and tumouristatic activities, as measured in a CFS-1 fibrosarcoma and a B16BL6 melanoma tumour model, respectively. These mutants also conserved their anti-angiogenic activity, as measured in an in vitro endothelial morphogenesis assay.26 In contrast, the pro-metastatic activity of the T104A and the triple mTNF mutants in the CFS-1 fibrosarcoma and the 3LL-R Lewis lung carcinoma tumour model was significantly lower than that of the wt molecule. These results thus indicate that the lectin-like domain of TNF is not implicated in its necrotic, tumouristatic and anti-angiogenic activities, but that it can contribute to the pro-metastatic effect of the cytokine. In conclusion, in view of their reduced systemic toxicity and pro-metastatic capacity, but their retained anti-tumour activities, lectin-deficient TNF mutants might prove to be therapeutically interesting alternatives to wt TNF.
Keywords AnimalsCarcinoma, Lewis LungCattleCell AdhesionCollagen/metabolismDose-Response Relationship, DrugEndothelium, Vascular/cytology/metabolismFemaleFibrosarcoma/genetics/metabolismLectins/metabolismLung/metabolismMelanoma, Experimental/genetics/metabolismMiceMice, Inbred C3HMice, Inbred C57BLMutationNecrosisNeoplasm MetastasisNeoplasm TransplantationNeoplasms, ExperimentalNeovascularization, PathologicProtein Structure, TertiaryRecombinant Proteins/metabolismTime FactorsTumor Cells, CulturedTumor Necrosis Factor-alpha/chemistry/genetics/therapeutic use
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PMID: 11251979
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LUCAS, Rudolf et al. Lectin-deficient TNF mutants display comparable anti-tumour but reduced pro-metastatic potential as compared to the wild-type molecule. In: International Journal of Cancer, 2001, vol. 91, n° 4, p. 543-9. https://archive-ouverte.unige.ch/unige:3857

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Deposited on : 2009-10-22

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