Mitomycin – Uses, Dosage, Side Effects, Interactions

Mitomycin is an antineoplastic antibiotic first isolated by Japanese microbiologists in the 1950s from cultures of Streptomyces caespitosus. It is an alkylating agent that inhibits DNA synthesis (and, at higher concentrations, RNA and protein synthesis) by cross-linking the complementary strands of the DNA double helix.^[rx] Few other antibiotics have been discovered that work via this alkylating mechanism, making mitomycin relatively unique in the space of microbiota-derived therapies.^[rx]

Mitomycin’s cross-linking activity has resulted in its approval for the treatment of a variety of cancers – the most recent of which is an April 2020 approval for its use in low-grade Upper Tract Urothelial Cancer (LG-UTUC)^[rx] – as well as adjunctly to ab externo glaucoma surgeries.

Potential bis-alkylating heterocyclic quinones were synthesized in order to explore their antitumoral activities by bioreductive alkylation.^[rx]

In the bacterium Legionella pneumophila, mitomycin C induces competence, a condition necessary for the process of natural transformation that transfers DNA and promotes recombination between cells.^[rx] Exposure of the fruitfly Drosophila melanogaster to mitomycin C increases recombination during meiosis, a key stage of the sexual cycle.^[rx] It has been suggested that during the sexual process in prokaryotes (transformation) and eukaryotes (meiosis), DNA cross-links and other damages introduced by mitomycin C may be removed by recombinational repair.^[rx]

Types

Mitomycin A

Mitomycins are antitumor antibiotics made by Streptomyces caespitosus (griseovinaceseus); Mitomycin C is used as an antineoplastic drug; [Merck Index] Mitomycins: Used as DNA alkylating/cross-linking agents;

Mitomycin B

Mitomycins are antitumor antibiotics made by Streptomyces caespitosus (griseovinaceseus); Mitomycin C is used as an antineoplastic drug; [Merck Index] Mitomycins: Used as DNA alkylating/cross-linking agents; [HSDB]

Mitomycin C

Mitomycin is one of the older chemotherapy? drugs, which has been around and in use for decades. It is an antibiotic that has been shown to have antitumor activity. Mitomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Mitomycin has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon-gamma, TNFa, and IL-2.

The drug inhibits DNA synthesis and cross-links DNA at the N6 position of adenine and at the O6 and N2 positions of guanine. In addition, single-strand breakage of DNA is caused by reduced mitomycin; this can be prevented by free radical scavengers. Its action is most prominent during the late G1 and early S phases of the cell cycle.

or

Mitomycin is an antibiotic that is isolated from the broth of Streptomyces caespitosus. This drug has demonstrated antitumor activity.[rx][rx] Mitomycin belongs to a group of alkylating agents that work by cross-linking the complementary strands found in DNA with absolute specificity and high efficiency for the CpG sequence.[rx]

Once activated by a reduction cascade, a series of spontaneous transformations cause mitomycin to attack DNA twice, resulting in cross-linking of strands of DNA double helix, thereby inhibiting DNA synthesis. Mitomycin is non-specific for a particular cell cycle phase but can exert its maximum effect in both the late G as well as the early S-phases.[rx]

It also suppresses RNA and protein synthesis at higher concentrations, hence being useful against some bacteria, spirochetes, and viruses. Lending to its toxic profile, mitomycin has a limited role as an antibiotic.[rx] Mitomycin also causes chromosomal breaks, thus leading to shortened strands of DNA, which eventually leads to chromosomal damage; this property renders mitomycin a potent carcinogen and teratogen.[rx]

In glaucoma surgery, the antifibrotic property of mitomycin prevents tissue scarring when surgeons create a surgical ocular flap to relieve excess fluid buildup.[rx]

Use in Cancer

Mitomycin is approved to be used alone or with other drugs to treat:

• Gastric (stomach) and pancreatic adenocarcinoma that is locally advanced or has metastasized (spread to other parts of the body). It is used in patients whose disease has not gotten better with other types of treatment.
• Urothelial cancer in the upper urinary tract. It is given directly into the ureter or kidney as a treatment for adults with low-grade disease. This use is approved for the Jelmyto brand of mitomycin.

Mitomycin is also being studied in the treatment of other types of cancer.

Contraindications

• Hypersensitivity to the active component or any of the ingredients
• In patients with thrombocytopenia, coagulation disorder, or an increase in bleeding tendency due to other causes
• a bad infection
• hemolytic uremic syndrome, a condition that affects the kidney and the blood
• decreased function of bone marrow
• anemia
• increased risk of bleeding due to clotting disorder
• an increased risk of bleeding
• decreased blood platelets
• low levels of white blood cells
• heart failure
• x-ray results showing lung tissue changes
• stomatitis, a condition with painful swelling and sores inside the mouth
• decreased kidney function
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage

Strengths: 5 mg; 20 mg; 40 mg; 1 mg/mL

Stomach Cancer

• After full hematologic recovery from any previous chemotherapy: 20 mg/m2 IV at 6- to 8-week intervals
• Because of cumulative myelosuppression, patients should be reevaluated after each course of this drug and the dose reduced if the patient has experienced toxicity.
• Doses greater than 20 mg/m2 have not been shown to be more effective and are more toxic than lower doses.
• For disseminated adenocarcinoma of the stomach in proven combination with other approved chemotherapeutic agents or as palliative treatment when other modalities have failed
• For disseminated adenocarcinoma of the pancreas in proven combination with other approved chemotherapeutic agents or as palliative treatment when other modalities have failed

Gastric Cancer

• After full hematologic recovery from any previous chemotherapy: 20 mg/m2 IV at 6- to 8-week intervals
• Because of cumulative myelosuppression, patients should be reevaluated after each course of this drug and the dose reduced if the patient has experienced toxicity.
• Doses greater than 20 mg/m2 have not been shown to be more effective and are more toxic than lower doses.
• For disseminated adenocarcinoma of the stomach in proven combination with other approved chemotherapeutic agents or as palliative treatment when other modalities have failed
• For disseminated adenocarcinoma of the pancreas in proven combination with other approved chemotherapeutic agents or as palliative treatment when other modalities have failed

Dose Adjustments

DOSE ADJUSTMENTS:
NADIR AFTER THE PREVIOUS DOSE:

• Leukocytes greater than 4000/mm3 and platelets greater than 100,000/mm3: Give 100% of the prior dose.
• Leukocytes 3000 to 3999/mm3 and platelets 75,000 to 99,999/mm3: Give 100% of the prior dose.
• Leukocytes 2000 to 2999/mm3 and platelets 25,000 to 74,999/mm3: Give 70% of the prior dose.
• Leukocytes less than 2000 and platelets less than 25,000/mm3: Give 50% of the prior dose.
• No repeat dosage should be given until the leukocyte count has returned to 4000/mm3 and platelet count to 100,000/mm3.
• When this drug is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly.
• If the disease continues to progress after 2 courses of this drug, therapy should be stopped since the chances of response are minimal.

Administration advice:

• Inspect visually for particulate matter and discoloration prior to administration.
• Give this drug IV only and avoid extravasation. If extravasation occurs, cellulitis, ulceration, and slough may result.

Reconstitution/preparation techniques:

• Each vial contains either mitomycin 5 mg and mannitol 10 mg, mitomycin, 20 mg and mannitol 40 mg or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 10 mL, 40 mL or 80 mL respectively. Shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until solution is obtained.
• The manufacturer’s product information should be consulted for more information.
• Avoid excessive heat (over 40C; 104F).
• Reconstituted with sterile water for injection to a concentration of 0.5 mg/mL is stable for 14 days refrigerated or 7 days at room temperature.
• This drug is stable in 0.9% sodium chloride injection for 12 hours.
• This drug is stable in sodium lactate injection for 24 hours.

Monitoring:

• Platelet count
• White blood cell count
• Differential
• Hemoglobin

Side Effects

The Most Common

• nausea
• vomiting
• loss of appetite or weight
• sores in the mouth and throat
• headache
• fainting
• blurred vision
• hair loss
• loss of strength and energy
• rash
• pain, itching, redness, swelling, blisters, or sores on the skin especially near the injection site
• shortness of breath
• difficulty breathing
• fast, irregular, or pounding heartbeat

Most  common

• Black, tarry stools
• blood in urine or stools
• signs of infection (fever, weakness, cold or flu symptoms, skin sores, frequent or recurring illness);
• wheezing, chest tightness, new or worsening cough, trouble breathing;
• blisters or ulcers in your mouth, red or swollen gums, trouble swallowing; or
• pain, burning, redness, swelling, irritation, or skin changes where the injection was given.
• cough or hoarseness
• fever or chills
• lower back or side pain
• painful or difficult urination
• pinpoint red spots on skin
• unusual bleeding or bruising

Rare

• Cough
• decreased urination
• shortness of breath
• sores in mouth and on lips
• swelling of feet or lower legs
• Bloody vomit
• Loss of appetite
• nausea and vomiting
• Numbness or tingling in fingers and toes
• purple-colored bands on nails
• skin rash
• unusual tiredness or weakness

Drug Interactions

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

Based on findings in animals and mechanism of action, JELMYTO can cause fetal harm when administered to a pregnant woman. There are no available data on JELMYTO use in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of mitomycin resulted in teratogenicity (see Data). Advise pregnant women of the
potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% – 4% and 15% – 20%, respectively.

Lactation

There are no data on the presence of mitomycin in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with JELMYTO and for 1 week following the last
dose.