The relevance of drug sequence in combination chemotherapy

The concept of combining chemotherapeutic agents to increase the cytotoxic efficacy has evolved greatly over the past several years. In the past, the rationale for combination chemotherapy centered on attacking different biochemical targets, overcoming drug resistance in heterogenous tumors, and increasing the dose-density of combination chemotherapy to take advantage of tumor growth kinetics. The overall goal was to improve clinical efficacy with acceptable clinical toxicity. It is now apparent that the sequence of drug administration can significantly enhance the therapeutic effect of chemotherapy. These sequence-dependent effects can be explained by chemotherapy-induced cell cycle perturbations, or by pharmacodynamic interactions between the agents in combination. In this review, we focus on drug combinations with taxanes and camptothecins, which we believe best illustrate the importance of the cell cycle and pharmacologic interactions in the sequential administration of chemotherapy. As our understanding of the cell cycle grows, our ability to appropriately sequence chemotherapy can have a great impact on the treatment of human cancers.