maytansine and Necrosis

Topics: Ado-Trastuzumab Emtansine; Female; Humans; Maytansine; Middle Aged; Necrosis; Skin; Trastuzumab

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFα in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFα enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs.

Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers; Cell Membrane; Cell Proliferation; Gene Expression; Hepatocytes; Humans; Immunohistochemistry; Inflammation; Liver; Maytansine; Membrane Potential, Mitochondrial; Mice; Microtubules; Mitochondrial Membranes; Models, Animal; Necrosis; Receptor, ErbB-2; Trastuzumab; Tubulin Modulators

In the last 10 years, multiple new targeted agents have been developed for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Up to 55% of patients with HER2+ breast cancer will develop brain metastases requiring some form of radiation therapy. The interaction between radiation and these targeted agents is unknown and previously unreported.. In this series, we describe 4 patients who developed clinically significant brain edema at sites of treated brain metastases. These patients were treated with stereotactic radiosurgery and trastuzumab emtansine, the newest FDA-approved agent for metastatic HER2+ breast cancer. Additionally, we present rates of clinically significant radiation necrosis among all breast cancer patients treated during this same time period.. Using previously published clinical and preclinical data, we then hypothesize possible mechanisms for this striking interaction.. Increased awareness of potential interactions between targeted agents and radiation to the brain is crucial.

Topics: Ado-Trastuzumab Emtansine; Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brain; Brain Edema; Brain Neoplasms; Breast Neoplasms; Combined Modality Therapy; Female; Humans; Maytansine; Middle Aged; Necrosis; Radiosurgery; Receptor, ErbB-2; Trastuzumab

The toxicity of maytansine given by sc administration was studied in 5-week-old mald F344 rats. The LD50 (14-day) was 0.48 mg/kg. A dose response to drug administration was indicated by body weight changes and diarrhea. A single, acutely toxic dose of maytansine was shown to possess marked activity against dividing cells which was regarded as an important factor in the pathogenesis of acute lesions in tissues with a normal high rate of cell division. Histologically, mitotic figues were observed in many tissues from 6 to 24 hours after drug administration. Subsequently, necrotizing lesions led to atrophic changes in gastrointestinal tract mucosa, thymus, spleen, bone marrow, and testis. Maytansine also induced hemorrhagic lesions in parenchymatous organs and brain and perivascular monomuclear infiltration in the meninges, and chromatolysis and vacuolation of dorsal root ganglion cells, accompanied by clinical signs of ataxia. Ulcerative skin lesions were observed at the sc site of drug administration.

Topics: Acute Disease; Animals; Atrophy; Body Weight; Bone Marrow; Cerebral Hemorrhage; Diarrhea; Dose-Response Relationship, Drug; Gastric Mucosa; Injections, Subcutaneous; Intestinal Mucosa; Male; Maytansine; Necrosis; Oxazines; Rats; Rats, Inbred F344; Spleen; Testis; Thymus Gland