T dm1 mechanism of action download#
It is an antibodydrug conjugate consisting of the monoclonal antibody trastuzumab linked to the cytotoxic. Download scientific diagram Mechanism of action of Trastuzumab-Emtasine (T-DM1). In Action Doge miner, you can hire other workers to complete your job. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. T-DM1 represents a new generation of cytotoxic drugs. If it doesnt work on your device/platform, you can help fix it by either getting. Preclinical studies demonstrate that T-DM1 has dual mechanisms of action: selective delivery of DM1 to the HER2-positive (HER2(+)) tumor cell combined with. Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. Trastuzumab emtansine (T-DM1, Kadcyla, Genentech, South San Francisco, CA, USA) is a new HER2-targeting immunotoxin which was developed through a combination of Trastuzumab (T) (Herceptin. In contrast, DM1 was only tolerated up to 0.2mg/kg (1600μgDM1/m2). T-DM1 was well tolerated at doses up to 40mg/kg (~4400μgDM1/m2) and 30mg/kg (~6000μgDM1/m2) in rats and monkeys, respectively. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies toxicity of DM1 was assessed in rats only. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Inhibition of microtubule polymerization. T-DM1 combines the same anti-HER2 properties of trastuzumab with the anti-tubulin properties of concentrated, high-dose DM1 chemotherapy. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. HER2 antitumor activities Disrupts ligand-independent HER2 signaling (antiproliferative and apoptotic effects) Mediates ADCC Inhibits HER2 shedding DM1 cytotoxic activity4 3. HER2 binding: Selectively binds to the HER2 receptor at subdomain IV. Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Proposed mechanism of action for KADCYLA Trastuzumab antibody activities4,10 1.
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