MESNA
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mesna uroprotection hemorrhagic cystitis
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Here is a comprehensive overview of MESNA:
MESNA (Sodium 2-Mercaptoethanesulfonate)
What Is It?
MESNA is a synthetic sulfhydryl (thiol) compound used as a uroprotective agent to prevent urothelial toxicity caused by oxazaphosphorine alkylating drugs - primarily ifosfamide and high-dose cyclophosphamide. The name is an acronym for MErcaptoSodium e-Acidic (or derived from its chemical name). Its trade name is Mesnex.
Mechanism of Action
Cyclophosphamide and ifosfamide undergo hepatic metabolism. The key toxic metabolite is acrolein (an alpha,beta-unsaturated aldehyde), which accumulates in urine and directly damages urothelial cells, causing hemorrhagic cystitis and, with prolonged exposure, bladder cancer.
How MESNA works:
- MESNA is administered IV or orally and rapidly oxidized in the plasma to its inactive disulfide form, dimesna
- Dimesna is filtered at the glomerulus and concentrated in the renal tubules
- In the urinary tract, dimesna is reduced back to the active free thiol (MESNA)
- The free thiol group (-SH) of MESNA binds covalently to acrolein in the urine, forming a stable, non-toxic thioether complex
- This inactivates acrolein locally in the urine without affecting systemic antitumor activity
This is the key elegance of MESNA: it acts as a urinary-tract-specific detoxifier. It does NOT interfere with the antineoplastic effects of cyclophosphamide or ifosfamide in the blood or tumors.
Clinical Uses
| Indication | Notes |
|---|---|
| Ifosfamide-induced hemorrhagic cystitis (primary, approved indication) | Mandatory co-administration with all ifosfamide regimens |
| High-dose cyclophosphamide (e.g., transplant conditioning, HSCT) | Standard of care; less clear benefit with low-dose oral cyclophosphamide |
| Rheumatologic use (pulse IV cyclophosphamide for vasculitis, SLE, Wegener's) | Widely used; RCT data from oncology extrapolated |
| Endoscopy adjunct | MESNA injected submucosally softens connective tissue (used in ESD procedures) |
Dosing
With Ifosfamide (Standard Regimen):
- IV bolus protocol: MESNA dose = 20% of ifosfamide dose, given at time 0, +4 h, and +8 h → total MESNA = 60% of ifosfamide dose
- Alternative: Single MESNA dose equal to 100% of ifosfamide dose given concomitantly
- Patients should also receive at least 2 L of oral or IV fluid daily
- Treatment cycles repeated every 3-4 weeks
With High-Dose Cyclophosphamide:
- Administered IV concomitantly; dosing varies by protocol
- For daily oral cyclophosphamide: oral MESNA given three times daily (though rarely used due to disagreeable taste)
Pharmacokinetics
- IV administration: rapidly oxidized to dimesna (inactive) in blood; selectively reduced back to MESNA in the urinary tract
- Oral bioavailability: approximately 45-79% (variable)
- Plasma half-life: short (about 1.2 h for MESNA, 70 h for dimesna)
- The short t½ is why multiple dosing or continuous infusion is needed to maintain protection throughout the period of urotoxic metabolite excretion
- Renal excretion is the primary route
Adverse Effects
MESNA is generally well tolerated. Reported adverse effects include:
- Nausea, vomiting, diarrhea (more common with oral form)
- Disagreeable taste with oral formulation (major limitation to oral use)
- Hypersensitivity reactions (rare)
- False-positive urine ketone test: MESNA contains free sulfhydryl groups that cross-react with nitroprusside-based urine dipstick tests (clinically important to know)
Important Clinical Points
- Does NOT protect against other toxicities of cyclophosphamide/ifosfamide (myelosuppression, nephrotoxicity, CNS effects from ifosfamide - which is managed with methylene blue)
- MESNA + IV hydration is the standard prophylaxis; hydration alone is insufficient for high-dose regimens
- For ifosfamide specifically, MESNA co-administration is considered mandatory; bladder toxicity was the original dose-limiting factor that restricted ifosfamide's use
- The evidence base for MESNA's efficacy comes primarily from ifosfamide studies and animal models; rheumatology data are supportive but less robust
- Bladder cancer risk from long-term cyclophosphamide is not fully mitigated by MESNA alone - treatment duration should be minimized
Sources:
- Goodman & Gilman's Pharmacological Basis of Therapeutics (Ch. 70 - Alkylating Agents)
- Firestein & Kelley's Textbook of Rheumatology (Urologic toxicity, Alkylating Agents sections)
- Lippincott Illustrated Reviews: Pharmacology
drugs used to ameliorate toxicities due to anti cancer drugs
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Drugs Used to Ameliorate Toxicities of Anticancer Drugs
These are "cytoprotective" or "chemoprotective" agents - drugs that reduce the adverse effects of chemotherapy without diminishing antitumor efficacy.
1. MESNA - Urotoxicity (Hemorrhagic Cystitis)
| Property | Detail |
|---|---|
| Anticancer drug | Cyclophosphamide, Ifosfamide |
| Toxicity prevented | Hemorrhagic cystitis (due to acrolein metabolite) |
| Mechanism | Free thiol group binds and inactivates acrolein in the urine; acts locally in urinary tract only |
| Dosing (ifosfamide) | 20% of ifosfamide dose IV at 0 h, +4 h, +8 h (total = 60%); or single dose equal to 100% of ifosfamide dose |
| Note | Does NOT interfere with antitumor activity; oral form has disagreeable taste |
- Goodman & Gilman's Pharmacological Basis of Therapeutics
2. LEUCOVORIN (Folinic Acid) - Myelosuppression & GI Toxicity
| Property | Detail |
|---|---|
| Anticancer drug | Methotrexate (high-dose); also used with 5-FU |
| Toxicity prevented | Bone marrow toxicity and GI mucositis |
| Mechanism | Leucovorin is an active (reduced) form of folate - bypasses the DHFR enzyme block caused by methotrexate, allowing normal cells to resume folate metabolism |
| Use | "Leucovorin rescue" - given within 24 h after high-dose MTX infusion; 15 mg/m² rescues from 10⁻⁸-10⁻⁶ M MTX with normal renal function |
| Note | Pemetrexed and pralatrexate require folic acid + vitamin B12 supplementation to reduce hematologic/GI toxicities |
- Lippincott Illustrated Reviews: Pharmacology; Brenner & Rector's The Kidney
3. DEXRAZOXANE - Cardiotoxicity
| Property | Detail |
|---|---|
| Anticancer drug | Doxorubicin (anthracyclines) |
| Toxicity prevented | Anthracycline-induced cardiomyopathy / heart failure |
| Mechanism | Iron chelation (prevents ROS generation via Fenton reaction) + inhibition of topoisomerase IIβ in cardiomyocytes (recently identified mechanism) |
| FDA approval | Only FDA-approved cardioprotectant for anthracyclines |
| Approved indication | Patients with metastatic breast cancer who have received >300 mg/m² of doxorubicin |
| Note | Also used as an extravasation rescue agent for anthracycline infiltration |
- Fuster and Hurst's The Heart, 15th ed.; Katzung's Basic & Clinical Pharmacology
4. AMIFOSTINE - Nephrotoxicity & Xerostomia
| Property | Detail |
|---|---|
| Anticancer drug | Cisplatin; also radiation (head and neck) |
| Toxicity prevented | Cisplatin-induced nephrotoxicity; radiation-induced xerostomia |
| Mechanism | Thiophosphate prodrug - dephosphorylated by alkaline phosphatase (more active in normal vs. tumor tissue) to free thiol, which scavenges free radicals and binds alkylating species |
| Key property | Selectively protects normal tissue over tumor tissue (due to differential alkaline phosphatase activity and poorer vascular supply in tumors) |
| Note | Does NOT protect against cisplatin ototoxicity; ototoxicity is unaffected by diuresis or amifostine |
- Goodman & Gilman's; Brenner & Rector's The Kidney
5. G-CSF / GM-CSF - Myelosuppression (Neutropenia)
| Agent | Class | Drug |
|---|---|---|
| Filgrastim | G-CSF (granulocyte CSF) | Stimulates neutrophil progenitors |
| Pegfilgrastim | Long-acting G-CSF | Once-per-cycle dosing |
| Tbo-filgrastim | G-CSF biosimilar | Similar to filgrastim |
| Sargramostim | GM-CSF | Stimulates granulocyte + monocyte progenitors |
-
Use: Prevention of febrile neutropenia after myelosuppressive chemotherapy; shortening neutropenia duration post-HSCT
-
Mechanism: Binds G-CSF receptors on neutrophil progenitors → stimulates proliferation, differentiation, and phagocytic activation of mature neutrophils
-
Katzung's Basic & Clinical Pharmacology; Lippincott Illustrated Reviews
6. OPRELVEKIN (IL-11, Neumega) - Thrombocytopenia
| Property | Detail |
|---|---|
| Anticancer drug | Any myelosuppressive chemotherapy for nonmyeloid malignancy |
| Toxicity prevented | Severe thrombocytopenia (platelet count <20 × 10⁹/L) |
| Mechanism | Recombinant IL-11 stimulates megakaryocyte proliferation and platelet production |
| Use | Administer until platelet count returns to >100 × 10⁹/L |
| Major complications | Fluid retention, atrial arrhythmias, conjunctival redness |
- Goodman & Gilman's (Interleukin-11 section)
7. ALLOPURINOL / RASBURICASE - Tumor Lysis Syndrome (Hyperuricemia)
| Agent | Mechanism | Use |
|---|---|---|
| Allopurinol | Xanthine oxidase inhibitor → blocks uric acid synthesis | Prevention of hyperuricemia pre-chemotherapy; moderate TLS risk |
| Rasburicase | Recombinant urate oxidase → converts uric acid to allantoin (highly soluble) | High TLS risk (high-grade lymphoma, ALL, bulky disease); faster and more effective than allopurinol |
-
Both combined with IV hydration ± urine alkalinization
-
Rasburicase is contraindicated in G6PD deficiency (allantoin metabolite causes hemolysis)
-
Brenner & Rector's The Kidney; Murray & Nadel's Respiratory Medicine
8. Antiemetics - CINV (Chemotherapy-Induced Nausea & Vomiting)
| Drug Class | Examples | Use |
|---|---|---|
| 5-HT₃ antagonists | Ondansetron, granisetron, palonosetron | Acute CINV (first 24 h); palonosetron also covers delayed |
| NK₁ receptor antagonists | Aprepitant, fosaprepitant, netupitant | Delayed CINV (>24 h); highly emetogenic regimens |
| Corticosteroids | Dexamethasone | Synergistic with 5-HT₃ and NK₁ antagonists in all phases |
| Dopamine antagonists | Metoclopramide, haloperidol | Breakthrough CINV |
| Cannabinoids | Dronabinol, nabilone | Refractory CINV |
-
ASCO 2011 guidelines: 5-HT₃ antagonist + NK₁ antagonist + dexamethasone for highly emetogenic regimens (e.g., cisplatin)
-
Goodman & Gilman's; Miller's Anesthesia
9. Other Specific Cytoprotectants
| Drug | Protects Against | Anticancer Drug | Mechanism |
|---|---|---|---|
| Folic acid + Vitamin B12 | Hematologic/GI toxicity | Pemetrexed, pralatrexate | Replenish folate pool |
| IV hydration + NaHCO₃ | Nephrotoxicity, uric acid precipitation | Cisplatin, MTX, high-dose regimens | Dilution + urinary alkalinization |
| Methylene blue | Ifosfamide encephalopathy | Ifosfamide | Reduces chloroacetaldehyde toxicity |
| Pyridoxine (Vit B6) | Peripheral neuropathy | Isoniazid (used alongside chemo in TB) | Repletes B6 depleted by drug |
| Calcium/Magnesium infusions | Neuropathy | Oxaliplatin | May reduce acute cold-triggered neuropathy (evidence debated) |
| Liposomal doxorubicin | Cardiotoxicity | (formulation change) | Reduces peak free doxorubicin levels |
Quick Reference Summary Table
| Toxicity | Causative Drug | Protective Agent |
|---|---|---|
| Hemorrhagic cystitis | Cyclophosphamide, Ifosfamide | MESNA |
| Bone marrow/GI toxicity | Methotrexate (high dose) | Leucovorin rescue |
| Cardiotoxicity | Doxorubicin (anthracyclines) | Dexrazoxane |
| Nephrotoxicity | Cisplatin | Amifostine, forced hydration |
| Neutropenia | Any myelosuppressive agent | Filgrastim / Pegfilgrastim (G-CSF) |
| Thrombocytopenia | Any myelosuppressive agent | Oprelvekin (IL-11) |
| Hyperuricemia / TLS | Cytotoxics (esp. lymphomas) | Allopurinol / Rasburicase |
| Nausea & vomiting | Cisplatin, anthracyclines, etc. | Ondansetron, Aprepitant, Dexamethasone |
| Encephalopathy | Ifosfamide | Methylene blue |
| Hematologic/GI toxicity | Pemetrexed | Folic acid + Vit B12 |
Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Katzung's Basic & Clinical Pharmacology; Lippincott Illustrated Reviews: Pharmacology; Fuster & Hurst's The Heart (15th ed.); Brenner & Rector's The Kidney; Miller's Anesthesia
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