Mechanism of Action of Cytarabine

Introduction

Cytarabine (also known as cytosine arabinoside or Ara-C) is a pyrimidine antimetabolite chemotherapeutic agent primarily used in the treatment of acute leukemias, especially acute myelogenous leukemia (AML). It is a cell cycle–specific drug, acting predominantly during the S-phase of the cell cycle. Cytarabine is a cornerstone drug in hematologic malignancies and is a high-yield topic in pharmacology, oncology, and hematology examinations due to its unique intracellular activation and DNA synthesis inhibition.

Mechanism of Action (Step-wise)

Cytarabine inhibits DNA synthesis by acting as a false nucleotide after intracellular activation.

Step-wise mechanism:

1. Cellular Uptake
   Cytarabine enters rapidly dividing cells via nucleoside transporters.
2. Intracellular Activation
   Inside the cell, cytarabine is phosphorylated by deoxycytidine kinase to form:
   • Cytarabine monophosphate (Ara-CMP)
   • Cytarabine diphosphate (Ara-CDP)
   • Cytarabine triphosphate (Ara-CTP) – the active metabolite
3. Competition with Deoxycytidine Triphosphate
   Ara-CTP competes with deoxycytidine triphosphate for incorporation into DNA.
4. Incorporation into DNA
   Ara-CTP is incorporated into the growing DNA strand during replication.
5. Inhibition of DNA Polymerase
   Incorporation of Ara-CTP inhibits DNA polymerase activity.
6. Premature Chain Termination
   Abnormal sugar moiety (arabinose) prevents proper elongation of the DNA strand.
7. S-Phase–Specific Cytotoxicity
   DNA synthesis is halted, leading to apoptosis of rapidly dividing leukemic cells.

Pharmacokinetics

• Administration: Intravenous, subcutaneous, intrathecal
• Absorption: Not effective orally due to rapid deamination
• Distribution: Widely distributed; penetrates CNS when given intrathecally
• Metabolism: Rapid hepatic deamination to inactive uracil arabinoside
• Elimination: Renal excretion
• Half-life: Short (10–20 minutes)
• Special feature: Requires continuous infusion or frequent dosing

Clinical Uses

Cytarabine is primarily used in hematologic malignancies:

• Acute myelogenous leukemia (AML) – first-line therapy
• Acute lymphoblastic leukemia (ALL)
• Chronic myelogenous leukemia (blast crisis)
• Non-Hodgkin lymphoma (selected regimens)
• Intrathecal use for leukemic meningitis

High-dose cytarabine is used in consolidation therapy for AML.

Adverse Effects

Cytarabine toxicity primarily affects rapidly dividing tissues:

• Hematologic:
  • Severe myelosuppression
  • Leukopenia
  • Thrombocytopenia
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Mucositis
• Neurologic (high-dose):
  • Cerebellar toxicity (ataxia, dysarthria)
• Ocular:
  • Chemical conjunctivitis
• Cytarabine syndrome:
  • Fever
  • Myalgia
  • Bone pain
  • Rash

Comparative Analysis (must include a table + explanation)

Comparison of Antimetabolite Chemotherapy Drugs

Explanation:
Cytarabine differs from other antimetabolites by acting directly as a false nucleotide incorporated into DNA. Its selective activity against rapidly proliferating leukemic cells makes it a mainstay in AML therapy, whereas methotrexate and 5-FU are more commonly used in solid tumors.

MCQs (10–15)

1. Cytarabine is classified as a:
   a) Alkylating agent
   b) Antitumor antibiotic
   c) Antimetabolite
   d) Mitotic inhibitor

Answer: c) Antimetabolite

2. Cytarabine is most active during which phase of the cell cycle?
   a) G₀
   b) G₁
   c) S
   d) M

Answer: c) S

3. The active metabolite of cytarabine is:
   a) Ara-CMP
   b) Ara-CDP
   c) Ara-CTP
   d) Uracil arabinoside

Answer: c) Ara-CTP

4. Cytarabine inhibits DNA synthesis by:
   a) Cross-linking DNA
   b) Blocking topoisomerase II
   c) Inhibiting DNA polymerase
   d) Inhibiting thymidylate synthase

Answer: c) Inhibiting DNA polymerase

5. Cytarabine is primarily used in:
   a) Breast cancer
   b) Lung cancer
   c) Acute myelogenous leukemia
   d) Colon cancer

Answer: c) Acute myelogenous leukemia

6. Cytarabine must be given parenterally because:
   a) Poor absorption
   b) Rapid hepatic deamination
   c) Renal toxicity
   d) High protein binding

Answer: b) Rapid hepatic deamination

7. A dose-limiting toxicity of cytarabine is:
   a) Nephrotoxicity
   b) Myelosuppression
   c) Cardiotoxicity
   d) Pulmonary fibrosis

Answer: b) Myelosuppression

8. High-dose cytarabine is associated with:
   a) Ototoxicity
   b) Cerebellar toxicity
   c) QT prolongation
   d) Peripheral neuropathy

Answer: b) Cerebellar toxicity

9. Cytarabine resembles which nucleoside?
   a) Adenosine
   b) Guanosine
   c) Cytidine
   d) Thymidine

Answer: c) Cytidine

10. Cytarabine is ineffective orally because of:
    a) First-pass metabolism
    b) Low lipid solubility
    c) Rapid deamination
    d) Poor stability

Answer: c) Rapid deamination

FAQs (minimum 5)

1. What is the primary mechanism of cytarabine?
   Inhibition of DNA synthesis by incorporation into DNA and inhibition of DNA polymerase.
2. Is cytarabine cell cycle–specific?
   Yes, it is S-phase specific.
3. Why is cytarabine mainly used in leukemia?
   Because leukemic cells divide rapidly and are highly sensitive to DNA synthesis inhibition.
4. What is cytarabine syndrome?
   A flu-like reaction with fever, myalgia, bone pain, and rash.
5. Why does high-dose cytarabine cause cerebellar toxicity?
   Due to accumulation in CNS tissues affecting neuronal function.
6. Can cytarabine be given intrathecally?
   Yes, for treatment of leukemic meningitis.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  https://accessmedicine.mhmedical.com
• Katzung BG. Basic and Clinical Pharmacology
  https://accessmedicine.mhmedical.com
• Tripathi KD. Essentials of Medical Pharmacology
  https://www.jaypeebrothers.com
• Harrison’s Principles of Internal Medicine
  https://accessmedicine.mhmedical.com

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