A 52-year-old man with newly diagnosed acute myeloid leukaemia (AML) presents to the haematology unit. His initial CBC shows WBC 85,000/µL with 70% blasts, Hb 7.2 g/dL, and platelets 35,000/µL. He is started on induction chemotherapy with cytarabine (Ara-C) and daunorubicin. On day 5 of therapy, he develops severe mucositis, diarrhoea, and hand-foot syndrome with erythema and blistering of palms and soles. His renal function remains normal. Which of the following best explains the mechanism of this toxicity?

Explanation

## Mechanism of Cytarabine (Ara-C) Toxicity ### Drug Activation and Action **Key Point:** Cytarabine is a cytidine analogue that requires intracellular phosphorylation by deoxycytidine kinase to become active. The active form (Ara-CTP) inhibits ribonucleotide reductase and gets incorporated into DNA. ### Mechanism of Toxicity Cytarabine's active metabolite (Ara-CTP) causes toxicity through: 1. **Ribonucleotide reductase inhibition** — blocks conversion of CDP to dCDP, reducing dNTP pools 2. **DNA chain termination** — Ara-CTP incorporates into growing DNA strands, causing chain elongation to stop 3. **Apoptosis induction** — rapidly dividing cells (bone marrow, GI epithelium, skin) undergo apoptosis due to incomplete DNA synthesis ### Clinical Manifestations of Cytarabine Toxicity | Toxicity | Mechanism | Timing | | --- | --- | --- | | **Mucositis** | GI epithelial apoptosis | Days 3–7 | | **Diarrhoea** | Intestinal crypt cell death | Days 3–7 | | **Hand-foot syndrome** | Palmar/plantar epithelial damage | Days 3–7 | | **Myelosuppression** | Bone marrow stem cell apoptosis | Days 5–14 | | **Neurotoxicity** (high-dose) | CNS penetration and toxicity | Dose-dependent | **High-Yield:** Ara-C toxicity is **dose-dependent**. High-dose Ara-C (≥3 g/m² per dose) carries significant risk of cerebellar syndrome and encephalopathy; standard-dose (100–200 mg/m²/day) causes mainly myelosuppression and mucositis. ### Why This Patient's Presentation Fits Ara-C - **Timing:** Day 5 of therapy — consistent with S-phase toxicity - **Pattern:** Mucositis + diarrhoea + hand-foot syndrome — classic triad of antimetabolite toxicity in rapidly dividing epithelial tissues - **Sparing of renal function:** Ara-C does not cause direct nephrotoxicity **Clinical Pearl:** Hand-foot syndrome (palmoplantar erythrodysesthesia) is a hallmark of antimetabolite and some targeted therapy toxicity. It reflects damage to eccrine sweat glands and dermal vasculature in high-turnover skin. ### Comparison with Other Antimetabolites | Drug | Mechanism | Toxicity Profile | | --- | --- | --- | | **Cytarabine (Ara-C)** | Ribonucleotide reductase inhibition + DNA chain termination | Mucositis, diarrhoea, hand-foot syndrome, myelosuppression | | **5-Fluorouracil (5-FU)** | Thymidylate synthase inhibition | Mucositis, diarrhoea, hand-foot syndrome, cardiotoxicity | | **Methotrexate** | Dihydrofolate reductase inhibition | Mucositis, myelosuppression, hepatotoxicity, nephrotoxicity | | **Mercaptopurine** | HGPRT-dependent purine antagonism | Myelosuppression, hepatotoxicity | **Mnemonic: CREAM** — **C**ytarabine (Chain termination), **R**ibonucleotide reductase inhibition, **E**ncephalopathy (high-dose), **A**ra-CTP (active form), **M**ucositis/Myelosuppression.