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Overview: rational integration of agents directed at novel therapeutic targets into combination chemotherapeutic regimens.

The last decade has witnessed the introduction of a number of agents directed against novel targets into the therapeutic armamentarium for the treatment of cancer. These include agents that interrupt neoplastic cell-survival signaling or cell-cycle regulatory pathways, and differentiation-inducing agents. A common theme linking these agents is that disruption of signal-transduction-, cell-cycle-progression- or differentiation-related pathways frequently leads to mitochondrial damage and apoptosis, and loss of neoplastic cell self-renewal capacity. It has also become apparent that these novel agents may, in a dose- and sequence-dependent manner, lower the threshold for conventional cytotoxic drug-induced apoptosis, resulting in synergistic interactions. More recently, evidence has been accumulating that the judicious combination of agents that interrupt more than one signaling-, cell-cycle-regulatory- or differentiation-related pathway represents an extremely potent apoptotic stimulus for neoplastic cells. The development of rational chemotherapeutic regimens combining these novel agents with others in their class or with conventional cytotoxic drugs presents significant challenges, but offers significant opportunities for therapeutic advances in the treatment of human malignancies. A brief overview of the status of this field follows.