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Molecular-biological approaches to the development of new anticancer agents

Research project P4/26 (Research action P4)

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Therapy of cancer requires that ways are found to selectively kill cancer cells without affecting normal cells. Recent findings on the normal life and death cycle of cells open new perspectives to achieve this goal.

Cancer cells have the ability to multiply in an unlimited and uncontrolled fashion. Moreover, in contrast to normal cells, they do not die when control mechanisms of the healthy body orders them to do so. Cells that are superfluous or harmful can indeed be given signals to die by either of two types of mechanisms called 'apoptosis' and 'necrosis', the first one being a silent death (sometimes called programed cell death) and the second one being a violent kind of death.

Our understanding of these mechanisms owes much to research on a substance called 'Tumor Necrosis Factor' or TNF, which is produced by white blood cells in defense against harmful agents such as cancer cells. Research on TNF has revealed that it can trigger both the apoptotic and the necrotic pathways, mainly depending on the type of cell. It has also appeared that, in fulfilling its role as a defence factor, TNF is aided by other more or less similar substances, collectively called 'cytokines'. One such cytokine is interferon-gamma (IFN-gamma ).

The partners in the IAP project have actively contributed to characterizing the nature and workings of these and other cytokines. In order to find ways for using appropriately these molecules in the clinic, they now join forces by further analysing the mechanisms of their production and their action.

Scientists of the pilot group (RUG) examine the structural basis by which TNF molecules interact with receptor molecules on target cells. They also study the intracellular cascade of events leading to cell death and to gene induction. In particular, they address the role of a class of protein-degrading enzymes called 'caspases', as well as that of damage to mitochondria as possible intermediate effectors of cell death. In addition, they study the fundamental mechanisms of cytokine-driven gene expression and regulation in an effort to specifically reduce side-effects. The KUL team (Protein Phosphorylation) participates in this endeavour by providing know-how to examine the role of phosphorylation reactions in transmitting the death signal from the membrane to the inner core of the cell.

The two other teams (KUL-Immunobiology and ULB), have elaborated experimental models in mice by which to analyse how TNF and IFN-gamma interact with each other and with other cytokines in the course of diseases. Release of cytokines in the intact body, although helpful in defence against cancer cells, also causes harmful inflammatory side reactions. In fact, excessive production of cytokines is held responsible for inflammatory damage in diseases such as arthritis and multiple sclerosis, as well as during graft rejection by transplant patients. The animal model systems developed by the satellite laboratories provide tools to define which cytokines are involved, in what sequence they exert their harmful effects, which other mediators are involved and how cytokines can be delivered in a non-harmful fashion.

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