Medical Pharmacology Chapter 33-34:  Anticancer Drugs

Previous Page Next Page
Section Table of Contents

Site Table of Contents

Mitomycin Pharmacology in Cancer Therapeutics

(Gemini AI Assisted) [May 13, 2025]
 

  • Overview

    • Mitomycin C (often referred to simply as mitomycin) is an antitumor antibiotic isolated from the bacterium Streptomyces caespitosus [1].

      • Mitomycin C functions as a potent DNA alkylating agent and has been a component of various cancer treatment regimens for decades.

        • Its unique mechanism of action, involving bioreductive activation, allows it to exert cytotoxic effects against a range of solid tumors.

  • Mechanism of Action

    • Mitomycin is a prodrug that requires intracellular enzymatic reduction to become a biologically active alkylating agent [1, 2]. Several key steps are involved in mitomycin mechanisms of action

      • 1.  Bioreductive Activation: In vivo, mitomycin undergoes a series of enzymatic reductions, primarily by NADPH-cytochrome P450 reductase and other quinone reductases like DT-diaphorase (NQO1) [3, 4].

        • This activation can occur under both aerobic and hypoxic conditions, though it is often more efficient in hypoxic environments found in solid tumors [4].

        • Reduction converts the inactive parent drug into highly reactive mono-, bi-, and potentially trifunctional alkylating species (e.g., a mitosene) [2, 3].

      • 2.  DNA Cross-linking: Once activated, mitomycin covalently binds to DNA, primarily at the N2 position of guanine residues, with a preference for CpG sequences [2, 5].

      • Both interstrand and intrastrand DNA cross-links may occur [1, 2].

        • These cross-links prevent the separation of DNA strands, thereby inhibiting DNA replication and transcription, and ultimately arresting cell division [1, 2].

        • Even a single interstrand cross-link per genome can be lethal to a cell [5].

      • 3. Inhibition of DNA, RNA, and Protein Synthesis: The primary cytotoxic effect is due to the inhibition of DNA synthesis resulting from DNA damage and cross-linking [1].

        •  At higher concentrations, mitomycin can also suppress RNA and protein synthesis [1]

      • 4.  Generation of Reactive Oxygen Species (ROS): Under aerobic conditions, the one-electron reduction product of mitomycin (semiquinone radical) can react with molecular oxygen to generate superoxide anions and other reactive oxygen species. These ROS can contribute to DNA damage and cellular toxicity [3, 4].

    • Mitomycin is generally considered cell-cycle phase-nonspecific, meaning it can damage cancer cells at various stages of the cell cycle [1].

  • Pharmacokinetics

    • Administration: Mitomycin is typically administered intravenously (IV) for systemic therapy [1].

      • Mitomycin can also be administered intravesically for the treatment of superficial bladder cancer, where it exerts a local effect with limited systemic absorption [2, 6].

        • Other specialized administrations include use in hyperthermic intraperitoneal chemotherapy (HIPEC) and as a pyelocalyceal solution for upper tract urothelial cancer [1, 7].

    • Distribution: After IV administration, mitomycin distributes widely into body tissues.

      • The highest concentrations are found in the kidneys, followed by muscle, eyes, lungs, intestines, and stomach.

        • Mitomycin does not significantly cross the blood-brain barrier [8].

        • Mitomycin can be taken up by erythrocytes [9]

    • Metabolism: Mitomycin is primarily metabolized in the liver by microsomal enzymes [1, 8].

      • However, enzymatic activation (reduction) also occurs in other tissues, contributing to its cytotoxic effects [8].

    • Excretion: Elimination of mitomycin occurs through metabolism and excretion in the urine.

      • Approximately 10% of an administered dose is excreted unchanged in the urine [1, 8].

      • A small portion may be eliminated in bile and feces [8].

      • The plasma half-life of mitomycin is relatively short, reported to be in the range of 8 to 55 minutes depending on the study and analytical methods [1, 9].

  •  Clinical Uses in Cancer Therapeutics

    • Mitomycin has demonstrated activity against a variety of solid tumors and is used in several clinical settings:

      • Gastrointestinal Cancers: It is used in combination chemotherapy regimens for advanced gastric, pancreatic, and anal cancers [1, 8, 10].

        • For anal cancer, mitomycin is a key component of the Nigro protocol, which combines it with 5-fluorouracil and radiation therapy [10].

      •  

        "Overview of Anal Cancer Chemoradiation Treatment"

      • Bladder Cancer: Intravesical instillation of mitomycin is a standard treatment for non-muscle invasive bladder cancer (NMIBC) following transurethral resection of bladder tumor (TURBT) to reduce the risk of recurrence [2, 6]. It is also used as a treatment for low-grade upper tract urothelial cancer (LG-UTUC) as a pyelocalyceal solution [1]

      • Breast Cancer: Mitomycin has been used in combination regimens for metastatic breast cancer, although its role has evolved with the advent of newer targeted therapies [1]

      • Lung Cancer: It has been incorporated into some chemotherapy regimens for non-small cell lung cancer (NSCLC), often in combination with drugs like ifosfamide and cisplatin (e.g., MIC regimen) [9].

      • Other Cancers: Mitomycin has also shown activity in cervical cancer and has been used in palliative settings for various other solid tumors [1].

        • Mitomycin is generally not indicated as a single-agent primary therapy for most cancers but is used in combination with other chemotherapeutic agents or modalities [8].

    • Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Mitomycin is one of the commonly used chemotherapeutic agents in HIPEC, a procedure where heated chemotherapy is delivered directly into the abdominal cavity after cytoreductive surgery for peritoneal malignancies [7].

    • Ophthalmic Use: Topically, mitomycin C is used in eye surgery (e.g., glaucoma filtering surgery, photorefractive keratectomy) to prevent scarring [2].

  • Adverse Effects

    • The use of mitomycin is associated with several significant toxicities, some of which can be severe and life-threatening:

      • Myelosuppression: This is the most common and serious dose-limiting toxicity.

        • Myelosuppression may be delayed, with nadirs for leukopenia and thrombocytopenia typically occurring 3-8 weeks after administration, and can be cumulative with successive doses [8, 11].

          • Anemia also occurs frequently [11].

      • Gastrointestinal Toxicity: Nausea, vomiting, anorexia, stomatitis (mouth sores), and diarrhea are common [8, 11].

      • Renal Toxicity: Mitomycin can cause kidney damage, leading to a rise in serum creatinine.

        • Hemolytic Uremic Syndrome (HUS), a serious and potentially fatal complication characterized by microangiopathic hemolytic anemia, thrombocytopenia, and irreversible renal failure, has been reported, particularly with cumulative doses exceeding 60 mg [8, 11]

      • Pulmonary Toxicity: Interstitial pneumonitis, pulmonary edema, acute respiratory distress syndrome (ARDS), and nonproductive cough can occur, though infrequently.

        • The risk may be increased at higher doses or when used in combination with vinca alkaloids or in patients receiving high concentrations of oxygen perioperatively [8, 11, 12]

      • Extravasation and Skin Toxicity: Mitomycin is a potent vesicant.

        • Extravasation (leakage outside the vein during IV administration) can cause severe local tissue damage, including pain, cellulitis, ulceration, and necrosis, which may be delayed in onset [11].

        • Skin rashes and alopecia (hair loss) can also occur [8, 11].

      • Cardiotoxicity: Congestive heart failure has been reported, especially at higher cumulative doses or in patients with pre-existing cardiac conditions [11]

      • Intravesical Administration Side Effects: When administered directly into the bladder, mitomycin can cause chemical cystitis, bladder discomfort, hematuria, urinary frequency, and rarely, bladder wall fibrosis or contraction [1, 6].

      • Allergic Reactions: Though uncommon, allergic reactions can occur [1].

  • Mechanisms of Resistance

    • The development of resistance to mitomycin can limit its clinical efficacy. Several mechanisms have been implicated:

      • Decreased Drug Activation: Cancer cells may exhibit reduced levels or activity of the enzymes required for the bioreductive activation of mitomycin (e.g., DT-diaphorase) [3, 4].

        • Reduced enzymic activity or amount of enzyme may lead to reduced formation of the active alkylating species.

      • Increased Drug Efflux: Overexpression of multidrug resistance proteins, such as P-glycoprotein, can actively pump mitomycin out of cancer cells, reducing its intracellular concentration.

      • Enhanced DNA Repair: Increased efficiency of DNA repair pathways (e.g., those involved in repairing interstrand cross-links) can allow cancer cells to survive mitomycin-induced DNA damage.

      • Increased Detoxification/Inactivation: Some cells may possess mechanisms to detoxify mitomycin or its active metabolites.

        •  For instance, the bacterial MCRA protein confers resistance by reoxidizing the reduced, cytotoxic hydroquinone intermediate back to the less toxic parent drug; analogous mechanisms might exist in mammalian cells [3, 4].

  • Conclusion

    • Mitomycin C remains a clinically useful chemotherapeutic agent for a variety of solid tumors, particularly in combination regimens and specialized local applications like intravesical therapy.

      • Its mechanism, centered on bioreductive activation and subsequent DNA cross-linking, provides a distinct mode of action.

      • However, its use is associated with significant toxicities, most notably delayed and cumulative myelosuppression and the risk of Hemolytic-Uremic Syndrome (HUS), requiring careful patient monitoring and dose management.

      •  Understanding its pharmacology, including mechanisms of resistance, is crucial for optimizing its therapeutic application and developing strategies to improve patient outcomes.

References
 
Previous Page Next Page
Section Table of Contents

Site Table of Contents

References

  1. Wellstein A Giaccone G Atkins MB Sausville Chapter 66:  Cytotoxic Drugs in Goodman & Gilman's:  The Pharmacological Basis of Therapeutics, 13e, Brunton LL Hilal-Dandan R Knollmann BC, eds) 2018.

  2. Sausville EA Longo DL Chapter 103e Principles of Cancer Treatment, in Harrison's Online   (Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo,  J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 19th edition, The McGraw-Hill Companies, Inc. 2015.

  3. Chu E  Cancer Chemotherapy Chapter 54 in Basic & Clinical Pharmacology, 14 e (Katzung BG The McGraw-Hill Companies, 2018 (on-line edition)

  4. Collins JM Cancer Pharmacology Chapter 29 in Abeloff's Clinical Oncology (Niederhuber JE Armitage JO Doroshow JH Kastan MB Tepper JE, eds)  5e Elsevier Churchill Livingstone, Philadelphia, PA 2014.

  5. Wellstein A Giaccone G Atkins MB Sausville Chapter 67:  Pathway-Targeted Therapies:  Monoclonal Antibodies, Protein Kinase Inhibitors, and Various Small Molecules in Goodman & Gilman's:  The Pharmacological Basis of Therapeutics, 13e, Brunton LL Hilal-Dandan R Knollmann BC, eds) 2018.

  6. Mitomycin: Drug Monographs, Access Medicine, Wolters Kluwer Clinical Drug Information, 2019.

  7. Copur M Ramaekers R Crockett D Gauchan D Chapter 29:  Miscellaneous Chemotherapeutic Agents in DeVita, JR VT Lawrence TS Rosenberg SA, eds) 11e Wolters Kluwer Health 2018.

  8. Chabner BA Bleomycin, Yondelis, MMC Chapter 15 in:  Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice Chabner BA Longo DL, eds 6e Wolters Kluwer 2019.

  9. Roche VF Cancer and Chemotherapy Chapter 37 in Foye's Principles of Medicinal Chemistry (Lemke TL Williams DA Roche VF Zity SW, eds) Wolters Kluwer | Lippincott Williams & Wilkins, Health, Philadelphia, 7e, 2013.

  10. Mitomycins https://en.wikipedia.org/wiki/Mitomycins

  11. Ajani JA Winter KA Gunderson LL Pedersen J Benson AB Thoras Jr CR

  12. Mayer RJ Haddock MG Rich TA Willett C Fluorouracil, Mitomycin and Radiotherapy vs Fluorouracil, Cisplatin and Radiotheerapy for Carcinoma of the Anal Canal:  A Randomized Controlled Trial. JAMA, 299: 16 1914-1921 2008. https://www.ncbi.nlm.nih.gov/pubmed/18430910

  13. Ducreux M What is new in anal cancer in the last 12 months?  ESMO 20th World Congress on Gastrointestinal Cancer. ImedexCME. https://www.youtube.com/watch?v=AEajshWQiUI

  14. Joseph RW New Immunotherapy Approved for Metastatic Bladder Cancer (Atezolizumab). Mayo Clinic,  Published May 24, 2016. https://www.youtube.com/watch?v=K28GL5D6mUE

This Web-based pharmacology teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.  Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information.  Medical or other information  thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.