Targeted Therapy for Advanced Colorectal Cancer — More Is Not Always Better

During the past few years, the outlook for patients with colorectal cancer has brightened considerably. Fluorouracil, an inhibitor of thymidylate synthase (and therefore DNA synthesis), was until recently the only effective systemic treatment for this disease. Fluorouracil is usually administered with leucovorin (i.e., folinic acid), which appears to stabilize the binding of the drug to thymidylate synthase. Since 1996, three new cytotoxic drugs — capecitabine (an oral fluoropyrimidine), irinotecan (a topoisomerase I inhibitor that blocks DNA repair), and oxaliplatin (an inhibitor of DNA replication and possibly a down-regulator of the expression of thymidylate synthase) — have been introduced into clinical . . .