I now have all the information I need from Lippincott to write a comprehensive, simplified breakdown. Here is the full explanation:
5-Fluorouracil (5-FU) - Simplified from Lippincott Illustrated Reviews: Pharmacology
Source: Lippincott Illustrated Reviews: Pharmacology - Anticancer Drugs (Chapter 37)
What is 5-FU?
5-Fluorouracil is a pyrimidine antimetabolite - it mimics the natural pyrimidine uracil but has a fluorine atom instead of hydrogen at position 5 of the uracil ring. This small change makes it a "fake" building block that poisons the DNA-making machinery.
- It is itself inactive (a prodrug that needs intracellular conversion)
- It is cell cycle specific - works in the S phase
Clinical Uses
5-FU is used mainly for slow-growing solid tumors:
| Tumor | Notes |
|---|
| Colorectal carcinoma | Most common use; often combined with leucovorin + irinotecan |
| Breast carcinoma | Part of combination regimens |
| Gastric carcinoma | |
| Pancreatic carcinoma | |
| Ovarian carcinoma | |
| Superficial basal cell carcinoma | Applied topically |
Mechanism of Action (Step by Step)
This is the most important part - understand the pathway:
Step 1: 5-FU enters the cancer cell via a carrier-mediated transport system (not by passive diffusion).
Step 2 (Activation inside the cell):
- 5-FU → 5-FUR (5-fluorouridine) via uridine phosphorylase
- 5-FUR → 5-FUMP (monophosphate) → 5-FUDP → then reduced by ribonucleotide reductase to form 5-FdUMP (5-fluorodeoxyuridine monophosphate)
Alternatively, 5-FU can go via phosphoribosyl transferase directly to 5-FUMP.
Step 3 (The Kill):
- 5-FdUMP is the active metabolite
- It competes with dUMP (deoxyuridine monophosphate) for the enzyme thymidylate synthase
- Thymidylate synthase normally converts dUMP → dTMP (thymidine), an essential DNA precursor
- 5-FdUMP inhibits thymidylate synthase → no dTMP → no thymidine → "thymidine-less death"
Two additional killing mechanisms:
- 5-FU is incorporated into RNA - disrupts RNA processing and function
- Low levels are incorporated into DNA - a glycosylase excises the 5-FU → DNA strand damage
Key trick for exams: 5-FU blocks DNA synthesis by killing thymidylate synthase. Remember the phrase "thymidine-less death."
Leucovorin (Folinic Acid) - Potentiator
Leucovorin (folinic acid) is added to enhance 5-FU toxicity, not to rescue it (contrast with methotrexate where leucovorin rescues).
- Leucovorin stabilizes the binding of 5-FdUMP to thymidylate synthase (ternary complex becomes more stable)
- Standard regimen for advanced colorectal cancer: Irinotecan + 5-FU + Leucovorin (FOLFIRI)
Pharmacokinetics
| Parameter | Detail |
|---|
| Route | IV (oral not used - severe GI toxicity); Topical for skin cancer |
| Distribution | Penetrates well into all tissues including CNS |
| Metabolism | Rapidly metabolized in liver, lung, kidney |
| Elimination | Inactive metabolites excreted in urine |
| Key enzyme | Dihydropyrimidine dehydrogenase (DPD) - major catabolic enzyme |
DPD - Important Clinical Point
- High DPD levels = faster 5-FU breakdown = decreased bioavailability (treatment failure)
- DPD levels vary up to sixfold between individuals
- DPD deficiency = 5-FU accumulates = severe toxicity: pancytopenia, mucositis, life-threatening diarrhea
Adverse Effects
From the Lippincott summary table:
| Adverse Effect | Notes |
|---|
| Diarrhea | Very common, dose-limiting |
| Severe mucositis | Stomatitis (oral ulcers) |
| Myelosuppression | Especially with bolus dosing |
| Hand-foot syndrome | More common with continuous infusion (also called palmar-plantar erythrodysesthesia - erythematous desquamation of palms and soles) |
| Alopecia | Hair loss |
| Coronary vasospasm | Unique cardiac toxicity - rare but important |
Bolus vs. Infusion memory trick: Bolus = Bone marrow suppression (myelosuppression). Continuous infusion = Cutaneous (hand-foot syndrome).
Monitoring: CBC, renal function, hepatic function, diarrhea
Resistance Mechanisms
Resistance to 5-FU occurs via:
- Decreased conversion to active 5-FdUMP (enzyme deficiencies in activation pathway)
- Amplification or mutation of thymidylate synthase (less drug binding)
- Increased DPD activity (faster drug catabolism)
Capecitabine - The Oral Prodrug of 5-FU
| Feature | Detail |
|---|
| Classification | Fluoropyrimidine carbamate; oral prodrug of 5-FU |
| Uses | Colorectal cancer, metastatic breast cancer |
| Activation | Absorbed orally → converted to 5-FU by thymidine phosphorylase (concentrated in tumors) |
| Advantage | Tumor-specific activation (thymidine phosphorylase is higher in tumors) |
| Key difference | Hand-foot syndrome MORE common vs 5-FU; nausea, diarrhea, stomatitis, neutropenia less common |
Quick Summary Table
| Feature | 5-FU |
|---|
| Class | Pyrimidine antimetabolite |
| Prodrug? | Yes - activated intracellularly |
| Active metabolite | 5-FdUMP |
| Target enzyme | Thymidylate synthase |
| Cell cycle phase | S phase |
| Route | IV (topical for skin) |
| Potentiator | Leucovorin (stabilizes inhibition) |
| Unique toxicity | Coronary vasospasm |
| Bolus toxicity | Myelosuppression |
| Infusion toxicity | Hand-foot syndrome |
| DPD deficiency risk | Severe toxicity (pancytopenia, diarrhea) |
| Oral prodrug | Capecitabine |
