Mitomycin

Mitomycin is an antitumor antibiotic produced by Streptomyces caespitosus. It is a prodrug that requires reductive activation inside cells to become a potent DNA-alkylating agent.

Mechanism of Action

Bioreductive Activation:

Mitomycin is enzymatically reduced by NADPH-dependent reductases (and other cellular oxidoreductases) to generate reactive alkylating intermediates. This bioactivation occurs preferentially in hypoxic environments — a property that confers selectivity toward the poorly oxygenated core of solid tumors. The guanine and cytosine content of DNA correlates directly with the degree of cross-linking: GC-rich regions are preferentially targeted.

DNA Cross-Linking:

The activated species is a bifunctional and trifunctional alkylating agent. It forms interstrand and intrastrand cross-links, targeting:

• N6 position of adenine and O6 and N2 positions of guanine (primary cross-linking sites)
• Single-strand breaks are also caused by reduced mitomycin via a free-radical mechanism; these are preventable by free-radical scavengers

Cross-linking inhibits DNA replication and transcription, ultimately triggering apoptosis. Action is most prominent during late G1 and early S phases of the cell cycle, but mitomycin is considered cell cycle phase-nonspecific overall.

Additional Effects:

• At high concentrations, cellular RNA and protein synthesis are also suppressed
• Has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation, and to impair secretion of IFN-γ, TNF-α, and IL-2

Pharmacokinetics

Mitomycin is absorbed inconsistently from the gastrointestinal tract and must therefore be administered intravenously.

• Peak plasma concentration (Cmax): approximately 0.4 µg/mL after doses of 20 mg/m²; disappears rapidly from blood after injection.
• Volume of distribution / tissue distribution: widely distributed throughout the body. Highest concentrations in kidneys, followed by muscles, eyes, lungs, intestines, and stomach. The drug is not detectable in liver, spleen, or brain — these organs rapidly inactivate mitomycin. Does not cross the blood-brain barrier. Higher concentrations generally found in cancer tissue than in normal tissue.
• Protein binding: approximately 70–80%.
• Metabolism: primarily hepatic; approximately 20% hepatic extraction. Extensively metabolized (>90% of dose); inactivation products have not been fully identified. Bioactivation of mitomycin to its alkylating form by tumor cell sonicates requires hypoxic conditions and an NADPH-generating system.
• Clearance: approximately 0.3–0.4 L/hr/kg.
• Half-life (biphasic):
  • Alpha phase: 5–10 minutes (rapid tissue uptake and distribution)
  • Beta phase: approximately 46 minutes (terminal elimination)
  • Overall range reported: 8–48 minutes; plasma clearance half-time approximately 1 hour at 20 mg/m² doses.
• Excretion: approximately 10% of a dose excreted unchanged in urine; <10% recovered in bile. At lower doses (<2 mg/kg IV in rats), urinary recovery of unchanged drug is approximately 18% within 24 hours; at higher doses (8 mg/kg) up to 35% excreted unchanged in urine (none in feces).

Gastric Cancer:

• Combined with 5-FU for advanced disease
• Improves overall survival in some regimens

Pancreatic Cancer:

• Used with gemcitabine and other agents
• Modest benefit in some protocols

Bladder Cancer:

• Intravesical instillation for non-muscle invasive disease
• Response rates 30-60%

Other Cancers:

• Breast, ovarian, colorectal, lung cancer (various regimens)
• Rarely used as single agent

• Advanced gastric cancer
• Pancreatic cancer
• Non-muscle invasive bladder cancer (intravesical)
• Various other solid tumors (in combination regimens)

Usually used in combination with other chemotherapy agents.

• Severe hypersensitivity to mitomycin
• Severe bone marrow suppression
• Baseline creatinine >1.7 mg/dL or CCr <60 mL/min
• Pregnancy and breastfeeding

Dose-Limiting Toxicity:

• Delayed Myelosuppression: Often severe, with nadir at 3-4 weeks

Very Common:

• Severe bone marrow suppression (anemia, neutropenia, thrombocytopenia)
• Nausea, vomiting
• Fatigue
• Mucositis

Common:

• Diarrhea
• Alopecia
• Anorexia
• Weakness

Serious/Rare:

• Hemolytic Uremic Syndrome (HUS): Serious complication (~0.1-2%), potentially fatal
  • Microangiopathic hemolytic anemia
  • Thrombocytopenia
  • Renal failure
• Pulmonary Toxicity: Pneumonitis, fibrosis (rare, more common with higher cumulative doses)
• Cumulative Nephrotoxicity: Usually asymptomatic elevation of creatinine
• Extravasation: Vesicant - tissue damage
• Secondary Malignancies: Leukemia risk (rare)

IV Infusion:

• Typical: 10-20 mg/m² per dose
• Usually every 6-8 weeks
• Total cumulative dose usually limited to 50-60 mg/m² (renal/HUS risk)
• Given in combination with other agents in most regimens

Intravesical (Bladder):

• 40 mg in 40 mL sterile water
• Instilled into bladder for 1-2 hours weekly for 6 weeks
• Weekly for maintenance

Administration:

• IV: slow infusion (preferably via central line)
• Vesicant - risk of extravasation
• Do not administer as IV push

Dose Modifications:

• Reduce for myelosuppression or previous treatment
• Avoid if CCr <60 mL/min
• Monitor renal function closely

• Vinca alkaloids: Increased neurotoxicity and pulmonary toxicity
• Doxorubicin: Increased cardiotoxicity, pulmonary toxicity
• Radiation: Enhanced toxicity (avoid concurrent treatment)

Bone Marrow Monitoring (CRITICAL):

• CBC before each dose
• Monitor for delayed myelosuppression (nadir weeks 3-4)
• May have cumulative bone marrow suppression
• CBC at day 21 after treatment to monitor nadir

Hemolytic Uremic Syndrome (HUS) Prevention:

• Monitor for HUS: Microangiopathic hemolytic anemia, thrombocytopenia, renal failure
• Symptoms: Hemoglobinuria, jaundice, decreased urine output, hypertension
• Higher risk with cumulative doses >50 mg/m²
• Fatal cases reported - strict cumulative dose limits recommended
• No known prevention besides limiting dose
• Early recognition/intervention critical

Renal Function Monitoring:

• Baseline creatinine and CCr required
• Monitor regularly during treatment
• Contraindicated if CCr <60 mL/min
• Monitor for proteinuria

Pulmonary Toxicity:

• Acute pneumonitis with dyspnea, fever, cough
• Chronic fibrosis with progressive dyspnea
• Higher risk with cumulative doses >50 mg/m², concurrent vinca/doxorubicin, or prior radiation
• Monitor respiratory symptoms
• Baseline and periodic chest X-ray or CT if at risk

Extravasation:

• Vesicant - causes tissue necrosis
• Administer via central line if possible
• Monitor IV site continuously
• If extravasation:
  • Stop infusion immediately
  • Aspirate residual drug
  • Apply ice
  • Plastic surgery consultation for severe cases

Pregnancy:

• Teratogenic
• Effective contraception required
• Avoid first trimester if possible

Handling:

• Cytotoxic - protective equipment required
• Institutional chemotherapy handling protocols

Unreconstituted powder: Store at 15–30°C. Protect from light. Temperatures above 40°C should be avoided. Commercially available mitomycin powder is stable for at least 4 years at room temperature when stored properly.

After reconstitution: Use immediately. If necessary, reconstituted solution may be stored at 2–8°C for up to 8 hours. Protect from light. Discard unused portion.

At least 4 years (unreconstituted powder) when stored properly. Do not use after expiry date.

Prescription required. Hospital/oncology use only. Due to serious risks (HUS, pulmonary toxicity), careful patient selection and monitoring essential. Strict cumulative dose limits (typically 50-60 mg/m²) must be observed.