## Most Common Antimetabolite in Colorectal Cancer **Key Point:** 5-Fluorouracil (5-FU) remains the backbone of colorectal cancer chemotherapy globally and in India, despite the advent of newer agents. It is the most frequently used antimetabolite in this malignancy. ### 5-FU in Colorectal Cancer **Mechanism of Action:** - Pyrimidine antimetabolite that inhibits thymidylate synthase (TS) - Blocks dTMP synthesis, preventing DNA replication - Also incorporates into RNA, disrupting protein synthesis ### Standard Regimens 1. **5-FU monotherapy:** Palliative or adjuvant (older regimens) 2. **5-FU + Leucovorin (Folinic acid):** Enhances 5-FU efficacy by stabilizing the 5-FU–TS complex 3. **FOLFOX:** 5-FU + Leucovorin + Oxaliplatin (standard first-line for metastatic CRC) 4. **FOLFIRI:** 5-FU + Leucovorin + Irinotecan (alternative first-line) **High-Yield:** Although newer targeted agents (bevacizumab, cetuximab) and other chemotherapy drugs (oxaliplatin, irinotecan) are now combined with 5-FU, the antimetabolite itself remains the foundational component of virtually all CRC regimens. 5-FU is the most common antimetabolite in solid tumors. ### Why 5-FU Dominates in CRC | Feature | 5-FU | |---------|------| | **Efficacy** | Proven benefit in adjuvant and metastatic settings | | **Cost** | Inexpensive; accessible in resource-limited settings | | **Combination potential** | Synergizes with leucovorin, oxaliplatin, irinotecan | | **Historical precedent** | Gold standard for >30 years | **Clinical Pearl:** The addition of leucovorin (folinic acid) to 5-FU increases response rates by ~10% compared to 5-FU alone, making 5-FU + Leucovorin the minimum standard. Modern practice adds oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) for improved survival in metastatic disease. **Mnemonic — "5-FU for CRC":** **F**luorouracil is the **F**oundation of **C**olorectal **C**ancer therapy.
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