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Apoptosis Defects and Chemotherapy Resistance:
Molecular Interaction Maps and Networks
Yves Pommier, Olivier Sordet, Smitha Antony, Richard L Hayward and Kurt W Kohn
Oncogene. 2004 Apr 12;23(16):2934-49
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Abstract:
Intrinsic (innate) and acquired (adaptive) resistance to chemotherapy critically limits
the outcome of cancer treatments. For many years, it was assumed that the interaction of
a drug with its molecular target would yield a lethal lesion, and that determinants of
intrinsic drug resistance should therefore be sought either at the target level (quantitative
changes or/and mutations) or upstream of this interaction, in drug metabolism or drug
transport mechanisms. It is now apparent that independent of the factors above, cellular
responses to a molecular lesion can determine the outcome of therapy. This review will
focus on programmed cell death (apoptosis) and on survival pathways (Bcl-2, Apaf-1, AKT,
NF-kappaB) involved in multidrug resistance. We will present our molecular interaction
mapping conventions to summarize the AKT and IkappaB/NF-kappaB networks. They complement
the p53, Chk2 and c-Abl maps published recently. We will also introduce the 'permissive
apoptosis-resistance' model for the selection of multidrug-resistant cells.
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