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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: February 19, 2020.



Plicamycin, which was formerly known as mithramycin, is an antibiotic that is used as an anticancer agent in the therapy of testicular and germ cell cancers. Plicamycin causes acute hepatic injury that arises within days of starting therapy, but is usually transient and asymptomatic and rarely leads to jaundice. Plicamycin has not been approved for use as cancer chemotherapy in the United States, but continues to be used on an investigational basis.


Plicamycin (plye” ka mye’ sin), which was formerly known as mithramycin, is an antineoplastic antibiotic that was first isolated from fermentation extracts of Streptomyces plicatus. It acts by binding to helical double-stranded DNA and blocking RNA synthesis. It has potent antitumor effects in vitro and has been evaluated in several solid tumors in humans. Because of its toxicities (including hepatotoxicities), it has not been approved for use in the United States. Nevertheless, plicamycin has distinctive and sometimes potent activities against germ cell and testicular cancers and continues to be investigated as an experimental therapy in patients with advanced and resistant forms of cancer. Plicamycin is also effective in reducing hypercalcemia associated with malignancy, probably by inhibition of osteoblast function, but its use has been replaced by less toxic approaches such as corticosteroids and bisphosphonates. For the treatment of cancer, plicamycin is administered intravenously in doses of 25 to 50 μg/kg daily for 5 to10 days in 2 to 6 monthly courses. Side effects of plicamycin are common and often dose limiting, including bone marrow suppression, irritability, agitation, gastrointestinal upset, diarrhea, nausea, anorexia, weakness, fever, rash, epistaxis, bruising and hemorrhage.


Chemotherapy with plicamycin causes serum enzyme elevations in almost all patients who are treated for more than 1 or 2 days and who are monitored during therapy. Serum ALT, AST and LDH values begin to rise within 3 days of the first infusion and peak within 7 to 10 days at levels of 5 to 500 times the upper limit of the normal range (ULN). The elevations, however, are transient and resolve within 1 to 3 weeks and are rarely associated with symptoms or jaundice. Liver biopsies taken during these episodes usually demonstrate centrolobular necrosis and congestion. With repeated courses, elevations continue to occur generally to the same or lesser degree. A single instance of acute liver failure arising within days of therapy that was suggestive of ischemic hepatitis or sinusoidal obstruction syndrome has been reported in a patient treated with full doses of plicamycin for 4 days for nonmalignant hypercalcemia. Otherwise, the serum enzyme elevations, despite being moderate to severe, are transient and benign.

Likelihood score: A[HD] (well known cause of clinically apparent liver injury with high dose intravenous treatment).

Mechanism of Injury

Plicamycin appears to be a direct, intrinsic hepatotoxin as the injury can be produced in animal models and occurs in almost all patients. The injury is likely to be dose related and is not more severe or more rapid in onset with rechallenge. Experimental studies suggest that the hepatotoxicity of plicamycin relates to inhibition of farnesoid X receptor signaling leading to deregulation of bile acid homeostasis.

Outcome and Management

The hepatic injury caused by plicamycin is usually reversible and requires no intervention. The hepatotoxicity of plicamycin has limited its usefulness, and it is considered contraindicated in patients with significant underlying liver disease.

Drug Class: Antineoplastic Agents

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


Case 1. Marked serum aminotransferase elevations during intravenous therapy with plicamycin.(1)

A 63 year old man with intrathoracic mesothelioma participating in a phase II clinical trial at the Clinical Center of the National Institutes of Health was started on intravenous plicamycin (25 mcg/kg/day) and developed marked serum aminotransferase elevations within 2 days. He had no history of liver disease, alcohol abuse or known drug allergies and was known to have normal liver tests before starting treatment. He had no symptoms of liver injury and was not receiving other medications. ALT levels peaked at 4832 U/L and AST levels at 4889 U/L a day after stopping therapy and then fell promptly (Table). Tests for hepatitis A, B and C were negative as were routine autoantibodies. Ultrasound of the liver suggested heterogeneity of the liver texture, but showed no other abnormalities, liver masses or evidence of obstruction. A liver biopsy showed centrolobular (zone 3) necrosis and hemorrhage with mild inflammation and no fibrosis or steatosis. After his serum enzymes returned to normal, he was rechallenged with a lower dose of plicamycin (18 mcg/kg/day) and serum aminotransferase levels again rose within a few days, but to a lesser degree (peak ALT 454 U/L). No further therapy with plicamycin was given.

Key Points

Pattern:Hepatocellular (R=193)
Severity:1+ (never jaundiced)
Latency:3 days
Recovery:Complete recovery within 4 weeks
Other medications:None

Laboratory Values

Time After
Time After
Alk P
PrePre32850.3Plicamycin started, INR 0.94
1 dayPre37680.6INR 0.89
2 daysPre48730.3
3 days0714750.3Ultrasound
4 days1 day4832710.6LDH 5995 U/L, liver biopsy
5 days2 days3510720.9INR 1.23
6 days3 days21441550.9
7 days4 days15221930.7
1 month26 days37800.6Plicamycin restarted
[3 days]142860.2INR 0.99
[5 days]4541260.4
Normal Values <42 <115 <1.2


The serial test results demonstrated the typical pattern of serum enzyme elevations with plicamycin therapy. The pattern is that of acute hepatic necrosis and is self-limited if therapy is stopped promptly. In this clinical trial, 10 of 12 treated patients developed hepatotoxicity with a pattern similar to the one shown. No patient developed jaundice, and symptoms, when present, were mild and nonspecific (mild nausea and abdominal discomfort).



Plicamycin – Generic, Mithracin®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Plicamycin 18378-89-7 C52-H76-O24 image 134992646 in the ncbi pubchem database


Sissung TM, Huang PA, Hauke RJ, McCrea EM, Peer CJ, Barbier RH, Strope JD, et al. Severe hepatotoxicity of mithramycin therapy caused by altered expression of hepatocellular bile transporters. Mol Pharmacol. 2019;96:158–67. [PMC free article: PMC6608607] [PubMed: 31175181]


References updated: 19 February 2020

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  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]
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  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. e7. [PMC free article: PMC4446235] [PubMed: 25754159]
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  • Sissung TM, Huang PA, Hauke RJ, McCrea EM, Peer CJ, Barbier RH, Strope JD, et al. Severe hepatotoxicity of mithramycin therapy caused by altered expression of hepatocellular bile transporters. Mol Pharmacol. 2019;96:158–67. [PMC free article: PMC6608607] [PubMed: 31175181]
    (12 patients with various malignancies were treated with 20 cycles of intravenous plicamycin of whom 10 developed ALT elevations that were above 5 times ULN in 8; molecular analyses suggested that the plicamycin hepatotoxicity was mediated by inhibition of FXR signaling: Case 1).


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