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Tuesday, August 19, 2025

Antineoplastic detoxifying agents


Introduction

Antineoplastic detoxifying agents are supportive drugs used in oncology to protect healthy tissues from the toxic effects of chemotherapy or to detoxify harmful metabolites of antineoplastic agents. They do not exert direct antitumor activity; instead, they function as rescue agents, antidotes, or protectants that enable oncologists to administer higher or more effective doses of chemotherapy while reducing life-threatening toxicities.

Their use is essential in minimizing dose-limiting side effects such as bone marrow suppression, nephrotoxicity, hemorrhagic cystitis, or mucositis. The clinical value of these agents lies in balancing efficacy and safety of chemotherapy protocols.

Classification of Antineoplastic Detoxifying Agents

  1. Folinic acid (Leucovorin, Calcium folinate, Sodium folinate) – Methotrexate rescue and 5-FU potentiation.

  2. Mesna (2-Mercaptoethane sulfonate sodium) – Prevention of ifosfamide/cyclophosphamide-induced hemorrhagic cystitis.

  3. Amifostine – Cytoprotective agent against cisplatin nephrotoxicity and xerostomia in radiotherapy.

  4. Dexrazoxane – Protects against anthracycline-induced cardiotoxicity and extravasation injury.

  5. Sodium thiosulfate – Reduces cisplatin-induced nephrotoxicity and hearing loss.

  6. Other adjunctive protectants (less common) – Glucarpidase (carboxypeptidase G2), used in high-dose methotrexate toxicity with renal impairment.

Mechanisms of Action

  • Leucovorin (folinic acid)

    • Rescues normal cells from high-dose methotrexate by bypassing inhibition of dihydrofolate reductase (DHFR).

    • Enhances binding of 5-fluorouracil (5-FU) to thymidylate synthase, increasing cytotoxic efficacy.

  • Mesna

    • Contains a sulfhydryl group that binds and detoxifies acrolein, the toxic metabolite of cyclophosphamide and ifosfamide, preventing hemorrhagic cystitis.

  • Amifostine

    • Prodrug converted to an active thiol metabolite (WR-1065) that scavenges free radicals and detoxifies reactive metabolites → protects kidneys from cisplatin and salivary glands from radiation-induced damage.

  • Dexrazoxane

    • Iron-chelating agent that reduces anthracycline-induced formation of free radicals in the myocardium.

    • Also protects tissue from anthracycline extravasation injury.

  • Sodium thiosulfate

    • Acts as a sulfur donor and neutralizes reactive platinum species, protecting against cisplatin-induced nephrotoxicity and ototoxicity.

  • Glucarpidase

    • Recombinant enzyme that rapidly hydrolyzes methotrexate into inactive metabolites in cases of toxic accumulation due to renal failure.

Clinical Uses

1. Leucovorin (Folinic Acid)

  • High-dose methotrexate rescue (osteosarcoma, leukemias, lymphomas).

  • Potentiation of 5-FU activity in colorectal cancer protocols (FOLFOX, FOLFIRI).

  • Treatment of folate deficiency megaloblastic anemia (when oral folate is not effective).

2. Mesna

  • Prevention of hemorrhagic cystitis caused by ifosfamide and cyclophosphamide.

  • Standard in all high-dose ifosfamide regimens.

3. Amifostine

  • Prevention of cisplatin-induced nephrotoxicity.

  • Reduction of xerostomia (dry mouth) in patients undergoing head and neck radiotherapy.

  • Protects bone marrow and normal tissues during radiotherapy and some chemotherapy regimens.

4. Dexrazoxane

  • Prevention of anthracycline-induced cardiotoxicity (e.g., with doxorubicin, epirubicin).

  • Management of anthracycline extravasation (infiltration into tissues).

5. Sodium Thiosulfate

  • Prevention of cisplatin nephrotoxicity and ototoxicity, particularly in pediatric oncology.

  • Treatment of cyanide poisoning (non-oncologic indication).

6. Glucarpidase

  • Treatment of toxic methotrexate levels in patients with renal dysfunction who cannot clear methotrexate normally.

Dosage Examples

  • Leucovorin:

    • Methotrexate rescue: 10–15 mg/m² IV/PO every 6 hours for 10–14 doses (adjusted by plasma methotrexate levels).

    • With 5-FU: 200–400 mg/m² IV over 2 hours, followed by 5-FU.

  • Mesna:

    • Given IV or orally at 20% of ifosfamide/cyclophosphamide dose at 0, 4, and 8 hours post-chemotherapy.

  • Amifostine:

    • 910 mg/m² IV, 15–30 minutes before cisplatin infusion.

    • 200 mg/m² daily during radiotherapy for xerostomia prevention.

  • Dexrazoxane:

    • Cardioprotection: 10:1 ratio with doxorubicin dose (e.g., 500 mg/m² dexrazoxane for 50 mg/m² doxorubicin).

    • Extravasation: 1000 mg/m² IV within 6 hours of extravasation, followed by doses at 24 and 48 hours.

  • Sodium Thiosulfate:

    • 16–20 g/m² IV infusion over 15 minutes, administered 6 hours after cisplatin infusion (dose varies by protocol).

  • Glucarpidase:

    • 50 units/kg IV over 5 minutes as a single dose.

Contraindications

  • Leucovorin: Pernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency.

  • Mesna: Hypersensitivity to mesna or thiol-containing compounds.

  • Amifostine: Hypotension, dehydration, hypersensitivity.

  • Dexrazoxane: Use not recommended in children receiving anthracyclines (risk of secondary malignancies).

  • Sodium thiosulfate: Caution in patients with severe electrolyte imbalance.

  • Glucarpidase: No absolute contraindications, but inappropriate use can interfere with methotrexate efficacy.

Adverse Effects

  • Leucovorin: Generally well tolerated; rare hypersensitivity reactions.

  • Mesna: Nausea, vomiting, headache, diarrhea, rash.

  • Amifostine: Hypotension (major limiting factor), nausea, vomiting, allergic reactions.

  • Dexrazoxane: Myelosuppression, nausea, vomiting, risk of secondary leukemia with long-term use.

  • Sodium thiosulfate: Metabolic acidosis, hypernatremia, nausea.

  • Glucarpidase: Allergic reactions, flushing, vomiting.

Precautions

  • Leucovorin: Must be dosed appropriately in methotrexate rescue—underdosing risks toxicity, overdosing may reduce antitumor efficacy.

  • Mesna: Adequate hydration is still required; mesna does not prevent nephrotoxicity.

  • Amifostine: Blood pressure monitoring is mandatory; premedication with antiemetics recommended.

  • Dexrazoxane: Reserved for patients with high cumulative anthracycline exposure due to concerns about interference with chemotherapy efficacy.

  • Sodium thiosulfate: Close monitoring of electrolytes.

  • Glucarpidase: Folinic acid (leucovorin) rescue must continue but not within 2 hours before or after glucarpidase administration.

Drug Interactions

  • Leucovorin:

    • Enhances 5-FU cytotoxicity (intended).

    • Antagonizes effects of methotrexate at high doses (rescue).

  • Mesna: No major drug–drug interactions.

  • Amifostine: Additive hypotension with antihypertensives.

  • Dexrazoxane: May potentiate myelosuppression when combined with chemotherapy.

  • Sodium thiosulfate: Can reduce cisplatin antitumor efficacy if administered simultaneously (must be delayed).

  • Glucarpidase: Inactivates methotrexate; leucovorin must be carefully timed to avoid neutralization.

Clinical Impact

These agents are not primary anticancer drugs but are critical in enabling safe and effective cancer therapy. For example:

  • Without mesna, high-dose ifosfamide would cause severe bladder toxicity.

  • Without dexrazoxane, cumulative anthracycline cardiotoxicity would limit dosing.

  • Leucovorin not only rescues normal cells from methotrexate but also enhances the efficacy of 5-FU in colorectal cancer.

Their use exemplifies the concept of supportive care in oncology—maximizing therapeutic benefit while reducing harm.




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