Therapeutic integration of signal transduction targeting agents and conventional anti-cancer treatments.

The currently available treatment of cancer patients is based on the use of cytotoxic drugs and/or of ionizing radiations, which have potent antitumor activity, but also cause clinically relevant side effects, since they affect cellular targets that are common to both cancer cells and normal proliferating cells. In the past 20 years, the discoveries on the molecular mechanisms of cancer development and progression have prompted the search for agents which are more selective for cancer cell molecular targets. The possibility of combining conventional cytotoxic drugs with novel agents that specifically interfere with key pathways controlling cancer cell survival, proliferation, invasion and/or metastatic spreading has generated a wide interest. This could be a promising therapeutic approach for several reasons. First, since the cellular targets for these agents and their mechanism(s) of action are different from those of cytotoxic drugs, it is possible for their combination with chemotherapy without cross-resistance. Second, alterations in the expression and/or the activity of genes that regulate mitogenic signals not only can directly cause perturbation of cell growth, but also may affect the sensitivity of cancer cells to conventional chemotherapy and radiotherapy. In this review, we will discuss the biologic bases of the combination of molecular targeted drugs with conventional medical cancer treatments and the available results of the first series of clinical trials in cancer patients.