Mitomycin

Publication Details

OVERVIEW

Introduction

Mitomycin is a cytotoxic antibiotic which is used as anticancer therapy of advanced cancers of the stomach and pancreas. Mitomycin in combination with other anticancer agents frequently causes mild-to-moderate serum enzyme elevations during therapy and is capable of causing sinusoidal obstruction syndrome, but mitomycin by itself has not been specifically linked to instances of clinically apparent liver injury with jaundice.

Background

Mitomycin (mye” toe mye’ sin), which is also called mitomycin-C, is a cytotoxic antibiotic first isolated from Streptococcus caespitosus and later shown to have potent antitumor effects in vitro and in vivo. Mitomycin has clinical activity against several forms of malignancy, and combination therapies that include mitomycin have proven effective in several forms of solid tumors. Mitomycin was approved for use in the United States in 2002 and current formal indications include advanced or disseminated stomach and pancreatic cancer in combination with other antineoplastic. Because of its toxicities, however, mitomycin is now rarely used. Mitomycin is available as a solution or lyophilized powder for injection in vials of varying concentrations generically and under the commercial name Mutamycin. The typical dose of mitomycin varies by indication and is adjusted for body weight and renal function. Side effects of mitomycin include bone marrow suppression, nausea, vomiting, diarrhea, stomatitis, rash, fever and malaise. Uncommon but potentially severe adverse events include hemolytic uremic syndrome, hemolysis, neurological abnormalities, renal failure and interstitial pneumonitis.

Hepatotoxicity

Chemotherapy with mitomycin in combination with other agents is associated with serum enzyme elevations in a proportion of patients, depending upon the dose and other agents used. ALT elevations during mitomycin therapy are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to mitomycin, because of the exposure to other potentially hepatotoxic agents. High doses of mitomycin have been linked to cases of sinusoidal obstruction syndrome, typically presenting with right upper quadrant pain 10 to 30 days after the infusion, followed by weight gain, ascites and liver test abnormalities. Fatalities due to hepatic failure have occurred, but most patients recover within 1 to 3 months of onset. The frequency of sinusoidal obstruction syndrome limits the dosage of mitomycin that can be used in cancer chemotherapy and in myeloablation in preparation for bone marrow transplantation. There have been no convincing instances of acute, clinically apparent idiosyncratic liver injury with jaundice associated with mitomycin therapy.

Likelihood score: B[H] (very likely but now uncommon cause of sinusoid obstruction syndrome when given in high doses and in combination with other cytotoxic agents).

Mechanism of Injury

Mitomycin can be directly toxic to cells and the transient liver enzyme elevations during therapy, and induction of sinusoidal obstruction syndrome are probably due to direct toxicity to hepatocytes and sinusoidal endothelial cells.

Outcome and Management

The hepatic injury due to mitomycin varies in severity from mild, transient and asymptomatic liver enzyme elevations to acute liver failure due to sinusoidal obstruction syndrome. There is no satisfactory therapy for sinusoidal obstruction syndrome besides careful management of fluid balance and avoidance of further injury. Sinusoidal obstruction syndrome has become rare, largely due to avoidance of high dose chemotherapy with agents that have been linked with it such as busulfan, cyclosphosphamide and mitomycin. Intravenous defibrotide has been used to treat severe sinusoidal obstruction syndrome with some evidence of partial response.

Drug Class: Antineoplastic Agents

Other Drugs in the Subclass, Antibiotics, Cytotoxic: Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Plicamycin

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Mitomycin – Generic, Mutamycin®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 19 February 2020

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    (Review of hepatotoxicity published in 1999 mentions that mitomycin produces steatosis in experimental animals and humans, but that this appears less important clinically than its potential for causing sinusoidal obstruction syndrome).
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