Enhancing the cytotoxic activity of novel targeted therapies--is there a role for a combinatorial approach?

The increased understanding of the pathogenetic and oncogenic pathways underlying cancer has allowed the successful development of novel approaches to treating the disease. The use of drugs to correct specific genetic defects responsible for the biological behaviour of cancer cells has been successfully applied to the clinic. These have included agents that interfere with cell proliferation and cell cycle signalling, neo-vascularisation, and DNA integrity. As a number of these processes also determine cellular survival, these novel agents can work to lower the cytotoxic threshold for conventional drugs. Consequently, a combinatorial drug approach could potentially be a valuable strategy for improving therapy. Unfortunately, targeting and inactivating a single pathway can adversely promote redundant parallel signalling pathways, which then maintain the aberrant status quo. Indeed, the intrinsic heterogeneity of tumours can preclude the successful application of a single targeted therapy. However, combinatorial drug approaches can be employed to surmount this multi-faceted characteristic of cancer. This article will highlight a number of novel targeted therapies that have been developed, some of which are currently undergoing clinical evaluation, and will also appraise the potential beneficial interactions that they may have with conventional cytotoxic drugs.