Perspectives on new chemotherapeutic agents in the treatment of colorectal cancer.

In patients with metastatic colorectal cancer (CRC), conventional chemotherapy with 5-fluorouracil (5-FU) plus leucovorin provides an overall response rate of approximately 25% but has had little effect on survival. Thus, alternate agents, new combinations of agents, and new treatment strategies are being investigated. Research efforts over the past decade have increased our understanding of how anticancer agents mediate their antitumor effects, and specific targets for inhibiting the survival, growth, or metastasis of CRC cells have been elucidated. Advances in our understanding have led not only to improvements in the application of currently available agents, but also to the discovery of new agents with activity in CRC. The following active areas of research and/or treatment approaches are discussed: (1) approaches for enhancing 5-FU/leucovorin activity; (2) novel delivery of 5-FU or 5-FU precursor agents; (3) new thymidylate synthase inhibitors; (4) new platinum analogues; (5) topoisomerase I inhibitors; (6) targeting specific proteins or pathways important for the growth, survival, or metastasis of CRC cells; (7) biologic response modifiers, including monoclonal antibodies; and (8) gene therapy. As the cellular mechanisms involved in CRC are further defined and chemotherapy or biologic agents more precisely targeted, response rates and ultimately survival will hopefully improve in this patient population.