In vitro: Trastuzumab has been demonstrated to exert a variety of anti-tumor effects selectively in HER2-overexpressing tumor cells. Trastuzumab binds to the juxtamembrane domain of HER2 and upon receptor binding, the antibody downregulates the expression of HER2. Trastuzumab selectively blocks ligand-independent HER2-HER3 dimerization. In addition, trastuzumab binding to HER2 blocks proteolytic cleavage of the extracellular domain of HER2, resulting in diminished levels of the more active p95-HER2 form of HER2. As a result of these effects on the HER2 receptor, trastuzumab causes downregulation of PI3K pathway signaling and downstream mediators of cell cycle progression such as cyclin D1. Trastuzumab not only inhibits HER2 signaling pathways but also triggers immune-mediated responses against HER2-overexpressing cells. Trastuzumab binding engages Fc receptors on immune effector cells leading to antibody-dependent cellular cytotoxicity. Beyond these effects, trastuzumab has been shown to have antiangiogenic effects and to lower the proapoptotic threshold for chemotherapy.
In vivo: Trastuzumab is shown to be safe when administered chronically to a range of animals including primates. In experiments mimicking adjuvant therapy of submacroscopic disease in vivo (JIMT-1 cells inoculated s.c. in severe combined immunodeficiency mice), trastuzumab is able to inhibit the outgrowth of macroscopically detectable xenograft tumors for up to 5-7 weeks. Trastuzumab has a remarkable antitumor effect and is currently used worldwide for the treatment of breast cancer. In in vivo models, trastuzumab decreases the microvessel density of breast cancer xenografts. It is well documented that trastuzumab acts directly in cancer cell signaling, as well as indirectly via the immune system.
|Cell lines||JIMT-1, SKBR-3, and BT-474 cells|
|Preparation method||Exponentially growing cells are harvested and plated in single wells of a 96-well flat-bottomed tissue culture plate at defined densities, ranging from 4,500–8,000 cells per well depending on the cell line. After overnight culture, the regular medium is exchanged to medium containing 0, 1, 10, or 100 μg/mL trastuzumab or trastuzumab-F(ab′)2. Cell viability is tested after 72 h of treatment. Fluorescence is detected at an excitation of 544 nm, and emission is detected at 590 nm.|
|Concentrations||0, 1, 10, or 100 μg/mL|
|Incubation time||72 h|
|Animal models||SCID C.B-17 scid/scid and nu/nmri nude mouse|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells.
Okita R, et al. Oncol Rep. 2015 Dec;34(6):2864-70. PMID: 26503698.
Tunicamycin enhances the antitumor activity of trastuzumab on breast cancer in vitro and in vivo.
Han X, et al. Oncotarget. 2015 Nov 17;6(36):38912-25. PMID: 26498681.
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