Introduction

The highly complex cellular regulatory networks and their interactions with small molecules present challenges to our mechanistic understanding of drug action. Deeper insights into the fundamental mechanisms of cellular functions and pathway regulations are likely to be critical for the development of rational approaches directed at the identification of molecular targets and candidate inhibitors. While the anti-tumor activity of current anti-cancer drugs is reflected in cell killing, mechanism-based studies attempt to specifically associate a drug's effect to one or many cellular regulation mechanisms (1). Individual protein targets of a small molecule may be involved in diverse cellular processes, some or all of which may contribute to the killing potential of a compound. Furthermore, environmental factors such as temperature, radiation, hypoxia, and nutrients, as well as drugs, stimulate an adaptive sensory and signaling machinery of the cell, and therefore may influence drug sensitivity, cell survival, and apoptosis.

The normal network structures of this system may be perturbed in diseases through genetic mutations and/or by pathological environmental cues such as infectious agents or chemical carcinogens. Cancer is believed to arise from multiple spontaneous and/or inherited mutations functioning in networks that control vital cellular events (2, 3, 4), which is partly reflected by genetic alterations in intracellular signaling pathways that normally control the developmental programs and the cellular response to extrinsic factors (5). The evolving states of certain cancers are reflected in dynamically changing expression patterns of genes and proteins within the cells (6).

An important challenge to associating gene expression in the context of biological processes involves the formulation of effective strategies to relate drug action to precise molecular targets. The notion of pathways (7) is a convenient abstraction that can both be considered in isolation and has been found useful in describing and understanding the inner workings of cellular biology (8,9). Because the biological response of a cell to a compound represents the whole organism readout of the drug's interaction within a cellular milieu, one approach is to utilize drug-gene pathway relationships to propose novel drug targets or target-specific drugs. For example, if a drug interacts with one gene product, the entire pathway or pathways having this gene may be disturbed, and a direct correlation between the drug and its target may not be apparent. Alternatively, the consequence of a drug action may be reflected by correlations of the drug response to other gene expressions within the pathways containing the putative target.

Cases where single drug-gene correlations are not directly apparent may be revealed by this broader examination of related genes within a pathway. The use of pathways also provides a central reference to a more systematic view of biological processes (7,10,11). Because cancer is a disease closely tied to genetic instability, the relative stability of pathways or pathway gene expression regulation is of great interest. The tendency for some pathways to change their behavior in cancer tissues compared to normal tissues may be a reflection of instability in the regulation of these pathways and represent potentially important and specific drug targets.

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