RESEARCH & DEVELOPMENT

Tumour necrosis £actor-a explained Combination therapy with tumour necrosis factor-a

(TNF-a) and inhibitors of the transcription factor nuclear factor lCB (NF-lCB) may result in a 'dramatic enhancement of killing' of tumour cells compared with therapy with TNF-a alone, report researchers from the US. 1

TNF is known to have several effects, including the activation of apoptosis and the activation of NF-lCB. However, trials of TNF-a alone in the treatment of cancer have yielded disappointing results to date.2 The results of studies conducted by 3 research teams in the US have demonstrated that the activation of NF-lCB contributes to this lack of efficacy. 1.3,4

Reduced viability In the first study, researchers demonstrated that the

viability of murine fibroblasts and macrophages that were deficient in NF-lCB was reduced, compared with normal cells, following treatment with TNF-a. 1

In another study, researchers engineered cells to express IlCBaM, an inhibitor of NF-lCB activation.3

Cells expressing IlCBaM were demonstrated to have a 'pronounced increase in sensitivity to TNF-a', compared with control cells.

In the final study, researchers established a human fibrosarcoma cell line that expressed a 'super-repressor' form of the NF-lCB inhibitor IlCBa.4

TNF-a was demonstrated to induce apoptosis more effectively in the cell line expressing the 'super-repressor' compared with in a control cell line.

Enhanced killing The researchers also demonstrated that NF-lCB can

be activated by ionising radiation and daunorubicin; in line with this observation, these agents were enhanced in their ability to induce apoptosis in cells expressing the • super-repressor' .

The results of these studies all support the idea that NF-lCB 'provides significant protection against apoptosis'.4 Thus, all the research teams conclude that a combination of TNF-a and an inhibitor of NF-lCB may have clinical utility in a variety of diseases, including cancer, bacterial and viral infections, and inflammatory disorders. 1. Beg AA. ct aL An essential role for NF-1(-B in preventing TNF-a-induced cell deaIh. Science 274: 782-784, I Nov 19961. Barinaga M. Life-<iealh balance within the cell. Science 274: 724, I Nov 1996 3. Van Antwerp OJ, et aI. Suppression ofTNF-a-induced apoplOsis by NF-1(-B. Science 274: 787-789, I Nov 1996 4. Wang C-Y, et aI. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition ofNF-1(-B. Science 274: 784-787, I Nov 1996 I0045I27'

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Inpharma-14 Dec 18116 No. 1067