Review Hepatotoxicity of molecular targeted therapy

Abstract

A constant increase in occurrence of neoplasms is observed; hence new methods of therapy are being intensively researched. One of the methods of antineoplastic treatment is molecular targeted therapy, which aims to influence individual processes occurring in cells. Using this type of medications is associated with unwanted effects resulting from the treatment. Liver damage is a major adverse effect diagnosed during targeted therapy. Drug-induced liver damage can occur as necrosis of hepatocytes, cholestatic liver damage and cirrhosis. Hepatotoxicity is evaluated on the basis of International Consensus Criteria. Susceptibility of the liver to injury is connected not only with toxicity of the used medications but also with metastasis, coexistence of viral infections or other chronic diseases as well as the patient's age. It has been proven that in most cases the liver injury is caused by treatment with multikinase inhibitors, in particular tyrosine kinase inhibitors. The Food and Drug Administration (FDA) ordered the inclusion of additional labels – so-called “black box warnings” – indicating increased risk of liver injury when treating with pazopanib, sunitinib, lapatinib and regorafenib. A meta-analysis published in 2013 showed that treating neoplastic patients with tyrosine kinase inhibitors can increase the risk of drug-induced liver damage at least twofold. Below the mechanisms of drug-induced liver injury and hepatotoxic effects of molecular targeted therapy are described.

The Human Cathelicidin Antimicrobial Peptide LL-37 and Mimics are Potential Anticancer Drugs

“…Cancer treatment strategies include radiation therapy, chemotherapy, and a combination of these, chemoradiotherapy, all of which exert cytotoxicity on cancer cells ( 39 , 40 ). In addition, specific inhibitors are available, which are used for cancer therapy, such as RTK or kinase inhibitors, in the form of monoclonal antibodies or small organic molecules ( 41 – 43 ). Although these treatments lead to improvements in many tumor types, they can cause severe side effects and delayed neurotoxicity owing to their non-specific mechanisms, which is the first crucial matter.…”

Incidence and risk of regorafenib-induced hepatotoxicity

“…So liver injury may be an attempting to kill cancerous cells, but generates more problems sometimes when the secondary hepatotoxicity becomes too severe [ 36 ]. Interestingly, it has been reported that in most cases hepatic AEs is caused by treatment with multi-kinase inhibitors, especial TKIs [ 37 ]. Previous studies have revealed that some TKIs such as imatinib [ 38 ] or pazopanib [ 39 ] can induce histologic alteration, inflammation, even acute liver failure in cancer patients.…”

Ibrutinib‐induced severe liver injury

“…Drug‐induced liver injury is mostly idiosyncratic and can present clinically as hepatocellular, cholestatic, or with mixed etiology . Mechanisms of hepatotoxicity can be variable.…”

“…Therefore, for patients with Child-Pugh score A, the recommended dose is 140 mg daily and should be avoided in patients with Child-Pugh classes B and C. Grade 4 increase in LFTs has been reported in a healthy subject after a dose of 1680 mg. Based on this, we could conclude that ibrutinib accumulates in an impaired liver and could also cause liver injury. Drug-induced liver injury is mostly idiosyncratic and can present clinically as hepatocellular, cholestatic, or with mixed etiology [12]. Mechanisms of hepatotoxicity can be variable.…”