Which antimetabolite is a pyrimidine analog that requires activation by thymidine kinase and is primarily used in hematologic malignancies?

Explanation

## Cytarabine: Mechanism and Clinical Role **Key Point:** Cytarabine (ara-C) is a **deoxycytidine (pyrimidine) analog** that is primarily activated by **deoxycytidine kinase** (with thymidine kinase playing only a minor, secondary role) to its active triphosphate form (ara-CTP), which inhibits DNA polymerase and causes chain termination. **High-Yield:** Cytarabine is the **gold standard antimetabolite for acute leukemias** (both AML and ALL) and is a cornerstone of induction and consolidation therapy in hematologic malignancies. ### Mechanism of Action 1. Converted to ara-CMP → ara-CDP → ara-CTP (active form) **primarily by deoxycytidine kinase** 2. ara-CTP inhibits DNA polymerase α → chain termination 3. Inhibits ribonucleotide reductase → ↓ dNTP pools 4. Incorporated into DNA → cytotoxicity 5. **Cell-cycle S-phase specific** > ⚠️ **Clarification:** The stem references "thymidine kinase" as the activating enzyme. While thymidine kinase can phosphorylate cytarabine to a minor extent, the **primary and rate-limiting activating enzyme is deoxycytidine kinase**. Among all options, cytarabine remains the only pyrimidine analog primarily used in hematologic malignancies (AML, ALL), making it the best answer. ### Clinical Applications - **Primary indication:** Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) - **High-dose toxicity:** Cerebellar syndrome, conjunctivitis (prophylaxis with lubricating eye drops) - **Intrathecal use:** CNS prophylaxis/treatment in leukemia ### Comparison with Other Options | Feature | Cytarabine | Gemcitabine | Fludarabine | Cladribine | |---------|-----------|------------|------------|----------| | **Analog type** | Pyrimidine (deoxycytidine) | Pyrimidine (deoxycytidine) | Purine (adenosine) | Purine (deoxyadenosine) | | **Primary activating enzyme** | Deoxycytidine kinase | Deoxycytidine kinase | Deoxycytidine kinase | Deoxycytidine kinase | | **Primary use** | AML, ALL | Solid tumors (lung, pancreas) | CLL, indolent lymphomas | Hairy cell leukemia, CLL | | **Dose-limiting toxicity** | Cerebellar syndrome (high-dose) | Myelosuppression | Neurotoxicity | Myelosuppression | **Clinical Pearl:** Cytarabine is the **only pyrimidine analog among the options** that is primarily used in hematologic malignancies (AML/ALL). Fludarabine and cladribine are purine analogs used in CLL/hairy cell leukemia, while gemcitabine is a pyrimidine analog used predominantly in solid tumors. [cite: KD Tripathi 8e Ch 65; Goodman & Gilman's Pharmacology 13e Ch 61]