Mechanism of Action of Doxorubicin

Mechanism of Action of Doxorubicin

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Introduction

Doxorubicin is a potent anthracycline antineoplastic antibiotic widely used in the treatment of a broad range of solid tumors and hematological malignancies. It is a cornerstone drug in many chemotherapy regimens due to its multiple cytotoxic mechanisms, but its use is limited by dose-dependent cardiotoxicity. Doxorubicin is a high-yield drug in pharmacology, oncology, and clinical entrance examinations because of its DNA-intercalating and topoisomerase II–inhibiting actions.

MOA of doxorubicin
MOA of doxorubicin
Doxorubicin Mechanism of Action Flowchart
Stepwise mechanism of action of doxorubicin

Mechanism of Action (Step-wise)

Doxorubicin exerts antitumor activity through multiple complementary mechanisms that disrupt DNA structure and function.

  1. DNA Intercalation
    Doxorubicin intercalates between adjacent base pairs of DNA.
  2. Distortion of DNA Helix
    Intercalation alters DNA conformation, interfering with replication and transcription.
  3. Topoisomerase II Inhibition
    Doxorubicin stabilizes the DNA–topoisomerase II complex after double-strand breaks.
  4. Prevention of DNA Resealing
    Inhibition of topoisomerase II prevents religation of DNA strands.
  5. Accumulation of DNA Breaks
    Persistent double-strand DNA breaks trigger apoptosis.
  6. Generation of Free Radicals
    Doxorubicin undergoes redox cycling, producing reactive oxygen species (ROS).
  7. Oxidative Damage to Cellular Components
    Free radicals damage DNA, proteins, and lipid membranes.
  8. Cardiotoxicity Mechanism
    Cardiac myocytes have low antioxidant defenses → ROS-mediated myocardial injury.

Pharmacokinetics

  • Administration: Intravenous only
  • Distribution: Extensive tissue binding; does not cross BBB effectively
  • Protein binding: Moderate
  • Metabolism: Hepatic metabolism to active and inactive metabolites
  • Elimination: Biliary excretion
  • Half-life: Triphasic (initial rapid, terminal prolonged)
  • Special note: Dose adjustment required in hepatic impairment

Clinical Uses

Doxorubicin is used in multiple malignancies:

  • Breast cancer
  • Hodgkin and non-Hodgkin lymphoma
  • Acute leukemias
  • Soft tissue and bone sarcomas
  • Ovarian cancer
  • Bladder cancer
  • Pediatric solid tumors

It is commonly included in combination regimens (e.g., ABVD, CHOP).

Adverse Effects

Adverse effects are dose-dependent and clinically significant:

  • Cardiac:
    • Dilated cardiomyopathy
    • Congestive heart failure (dose-limiting)
  • Hematologic:
    • Myelosuppression
  • Gastrointestinal:
    • Severe nausea and vomiting
    • Mucositis
  • Dermatologic:
    • Alopecia
  • Local:
    • Severe tissue necrosis with extravasation

Cardiotoxicity risk increases with cumulative dose.

Comparative Analysis (must include a table + explanation)

Comparison of Anthracycline Anticancer Drugs

FeatureDoxorubicinDaunorubicinEpirubicin
Primary mechanismDNA intercalation + Topo II inhibitionSimilarSimilar
Free radical generationHighModerateLower
Cardiotoxicity riskHighModerateLower
Common useSolid tumorsLeukemiasBreast cancer
LipophilicityModerateModerateHigher

Explanation:
Doxorubicin is the most potent but also the most cardiotoxic anthracycline. Epirubicin is preferred when lower cardiac toxicity is desired, while daunorubicin is mainly used in leukemias.

MCQs (10–15)

  1. Doxorubicin primarily acts by:
    a) Alkylating DNA
    b) Intercalating DNA and inhibiting topoisomerase II
    c) Blocking microtubules
    d) Inhibiting thymidylate synthase

Answer: b) Intercalating DNA and inhibiting topoisomerase II

  1. The enzyme inhibited by doxorubicin is:
    a) DNA polymerase
    b) RNA polymerase
    c) Topoisomerase II
    d) Topoisomerase I

Answer: c) Topoisomerase II

  1. Doxorubicin generates which harmful species?
    a) Nitric oxide
    b) Free radicals
    c) Carbon monoxide
    d) Hydrogen sulfide

Answer: b) Free radicals

  1. Cardiotoxicity of doxorubicin is mainly due to:
    a) Calcium channel blockade
    b) Free radical–mediated damage
    c) Mitochondrial inhibition
    d) Sodium channel blockade

Answer: b) Free radical–mediated damage

  1. Doxorubicin belongs to which drug class?
    a) Alkylating agent
    b) Antimetabolite
    c) Anthracycline antibiotic
    d) Vinca alkaloid

Answer: c) Anthracycline antibiotic

  1. A dose-limiting toxicity of doxorubicin is:
    a) Nephrotoxicity
    b) Cardiotoxicity
    c) Neurotoxicity
    d) Ototoxicity

Answer: b) Cardiotoxicity

  1. Doxorubicin is most commonly excreted via:
    a) Urine
    b) Sweat
    c) Bile
    d) Lungs

Answer: c) Bile

  1. Doxorubicin extravasation causes:
    a) Mild irritation
    b) Local vasodilation
    c) Severe tissue necrosis
    d) Immediate thrombosis

Answer: c) Severe tissue necrosis

  1. Doxorubicin is commonly used to treat:
    a) Prostate cancer
    b) Breast cancer
    c) Pancreatitis
    d) Asthma

Answer: b) Breast cancer

  1. Which drug reduces doxorubicin-induced cardiotoxicity?
    a) Leucovorin
    b) Mesna
    c) Dexrazoxane
    d) Allopurinol

Answer: c) Dexrazoxane

FAQs (minimum 5)

  1. What is the primary mechanism of doxorubicin?
    DNA intercalation and inhibition of topoisomerase II causing DNA strand breaks.
  2. Why is doxorubicin cardiotoxic?
    Due to free radical–mediated myocardial damage.
  3. Is doxorubicin cell cycle specific?
    No, it is cell cycle nonspecific.
  4. How is cardiotoxicity prevented?
    By limiting cumulative dose and using dexrazoxane.
  5. Does doxorubicin cross the blood–brain barrier?
    No, it has poor CNS penetration.
  6. Is doxorubicin bactericidal?
    No, despite being an antibiotic, it is used only as an anticancer drug.

References

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