Due to its superhelical structure, DNA requires an enzyme to introduce and reseal single-strand breaks as it unwinds for transcription or replication. This is accomplished by the enzyme, topoisomerase I. Irinotecan and its active metabolite bind to complexes of topoisomerase I and DNA, preventing the rejoining of the single-strand breaks created by the enzyme. This eventually leads to breakage in the double-stranded DNA structure and to the death of the cell. Irinotecan is an intravenously administered drug that is indicated for first-line therapy in combination with 5-FU and leucovorin for patients with metastatic carcinoma of the colon or rectum. It is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. In a phase 3 study conducted in patients who failed first-line 5-FU, irinotecan improved 1-year survival, median survival, and median progression-free survival compared to patients receiving continuous infusion 5-FU. In addition, in a study in patients with second-line refractory CRC, irinotecan was superior to supportive care in terms of overall survival. The prescribing information for irinotecan has a boxed warning related to the potential for diarrhea and severe myelosuppression. These are its most prominent side effects.