Nursing Pharmacology Chapter 33-34:  Anticancer Drugs

• Miscellaneous Anticancer Drugs: 

  • Mitomycin (Mitosol)

    • Mitomycins refer to a group of aziridine-containing natural products which are obtained from either Streptomyces caespitosus or Streptomyces lavendulae.¹⁰ 

      • The group consists of mitomycin A, mitomycin B, and mitomycin C.

        • The use of the term "mitomycin" alone usually refers to mitomycin C which is used clinically.¹⁰

    • Overview:

      • Mitomycin (mitomycin C, Mitosol) is classified as an antibiotic anticancer drug.³ 

        • This antibiotic was first isolated from Streptomyces caespitosus in 1958.^3,8 

        • Mitomycin is a prodrug requiring metabolic activation which, by means of a cytochrome P450-dependent enzyme catalyzed reduction, results information of a DNA cross-linking agent (alkylating agent).^3,9  

          • Hypoxic tumor stem cells associated with solid tumors tend to be hypoxic which results in an environment that promotes reductive reactions.

            • As a result, the cells tend to be more responsive to mitomycin cytotoxicity compared to normal cells or even the more oxygenated tumor cells.

            • Mitomycin is an effective antineoplastic agent in all phases of the cell-cycle and appears particularly efficacious when combined with radiation treatment directed at hypoxic tumor.

              • At present, this agent is primarily used in combination treatment for anal squamous cell cancer.

                • Mitomycin is combined with 5-fluorouracil and radiation in this setting.³

    • Absorption, Distribution, Biotransformation, Excretion:

      • Mitomycin is administered by the IV (intravenous) route of administration, exhibiting a t_½ of about 25-90 minutes.¹  

      • Mitomycin is widely distributed throughout the body but is not found in the central nervous system¹ 

      • Mitomycin undergoes liver metabolism and is mainly excreted in the feces and to a lesser extent in urine (10%) .^1,6

      • Additionally, mitomycin may also be inactivated through chemical conjugation with sulfhydryl groups.¹

    • Mechanism of Action:

      • As noted earlier, mitomycin is a "prodrug" and therefore requires activation to exert its antineoplastic activity.

        • This process involves NADPH/Cytochrome P450 reductase catalyze conversion of mitomycin to mitomycin hydroquinone.

          • This latter form interacts with DNA, forming the cross-linked DNA mitomycin-DNA adduct.⁹ 

    • Clinical Uses:

      • The principal clinical use of mitomycin is in the treatment of anal squamous cell carcinoma.¹⁴ 

        • Mitomycin is combined with 5-FU (5-fluorouracil) and radiation.

        • Anal canal carcinoma represents a rare malignancy in the United States.

          • This carcinoma has limited metastatic potential (about 15%), making it a "local-regional" cancer.

        • When chemotherapy is used along with radiation, cure rates approximate 60%, depending on the initial primary tumor size.

          • Five-year survival rates fall substantially for tumors greater than 5 cm in diameter.

            • A reduction in cure rate is also associated with nodal metastases.

              • Standard treatment involves mitomycin (along with 5-FU and radiation); however, substituting cisplatin results in a comparable disease-free-survival time but with the significantly worse colostomy rate.¹⁴

        • Advanced, Metastatic Anal Cancer

           

          • What is new in anal cancer in the last 12 months" Published on Aug 13, 2018¹³

            Attribution: Ducreux M What is new in anal cancer in the last 12 months?  ESMO 20th World Congress on Gastrointestinal Cancer. https://www.youtube.com/watch?v=AEajshWQiUI (5/2018) ImedexCME Youtube Channel:  https://www.youtube.com/channel/UChzdRqqisBHL_DgHGq0COFg

      • Superficial "transitional cell" carcinomas of the bladder may also be treated using mitomycin, by direct installation into the bladder.¹

        • Metastatic Bladder Cancer:

        • New Immunotherapy:  Metastatic Bladder Cancer¹⁴

          Attribution: Joseph RW New Immunotherapy Approved for Metastatic Bladder Cancer (Atezolizumab) https://www.youtube.com/watch?v=K28GL5D6mUE (5/2016) Mayo Clinic Youtube Channel:  https://www.youtube.com/channel/UC8fQzKHIhSoZeSq3bwQx4mw

      • Other clinical uses of mitomycin include:³ 

        • Combined with other chemotherapy drugs for cervical squamous cell carcinoma

        • Breast cancer

        • Gastric cancer

        • Pancreatic cancer³

    • Toxic/Adverse Reactions:

      • The major adverse, toxic reaction to mitomycin administration is myelosuppression.

        • This myelosuppression is associated both with significant leukopenia and thrombocytopenia.

          • Myelosuppression may be both delayed and cumulative with an extended recovery time that may include 6-8 weeks of pancytopenia.¹

      • Other adverse effects include¹ :

        • Stomatitis

        • Nausea

        • Diarrhea

        • Vomiting

        • Rash Fever.

      • At higher doses (>50 mg/m²) a patient may be at risk for:¹

        • Hemolysis

        • Interstitial pneumonia

        • Neurological dysfunction

        • Renal failure, secondary to glomerular damage.

          • At the higher doses, 70 mg/m² about 28% of patients may experience renal failure.¹

        • A "Hemolytic-Uremic Syndrome" has been identified, presenting as microangiopathic hemolytic anemia, along with thrombocytopenia and renal failure.³

          • This syndrome may, on occasion, present with interstitial pneumonitis.³