Lapatinib is a potent purified EGFR and ErbB-2 inhibitor with IC50 of 10.2 and 9.8 nM, respectively. Lapatinib is >300-fold selective for EGFR and ErbB-2 over other kinases tested such as c-Src, MEK and ERK, except for ErbB-4. Lapatinib prevents receptor autophosphorylation of EGFR and ErbB-2 in a dose-responsive manner with IC50 of 0.17 and 0.08 μM against BT474 and HN5 cell lines, respectively. The ability of Lapatinib to blocks EGFR and ErbB-2 autophosphorylation in EGFR- and ErbB-2-overexpressing tumor cells is ∼10-fold less than its potency on the purified enzyme. The ErbB-2-transfected mammary epithelial cell line, HB4a c5.2, is ∼40-fold more responsive to Lapatinib treatment than the untransfected parental control line, HB4a. Transient exposure to 30 μM Lapatinib results in complete inhibition of outgrowth of the HN5 cell population after ∼2 additional weeks of culture without Lapatinib. Lapatinib inhibits tumor growth by 50% occurs at concentrations of >3.3 μM. Significant prevention of outgrowth (20%) occurs at doses as low as 0.37 μM. Lapatinib is similar to OSI-774 in its ability to inhibit outgrowth of the EGFR-overexpressing cell line. Lapatinib is potent at inhibiting the growth of BT474 and HN5 human tumor xenografts. A dose-responsive inhibition of both models occurs on treatment of tumor-bearing mice with 30 and 100 mg/kg Lapatinib orally, twice daily. Lapatinib at the dose of the 100 mg/kg completely inhibits the growth of tumor. At this dose, there is <10% weight loss in treated animals over the course of the 21-day treatment. Lapatinib has been approved for HER-2-positive metastatic breast cancer. Lapatinib has entered in a phase III clinical trial for the treatment of HER2+ metastatic breast cancer.
Cancer Cell. 2015 Jan 12;27(1):97-108.
|Source||Cancer Cell (2015). Figure 3. Lapatinib (Abmole)|
|Cell Lines||BT-474, SKBR3 cell|
|Incubation Time||24 h|
|Results||This led to the loss of p110b recruitment and the block of the rebound of AKT activation observed 24 hr after treatment with BYL719 alone.|
|Cell lines||HFF, MCF-7, T47D, A-431, HN5, BT474, N87, CaLu-3, HB4a, and HB4a c5.2 cells|
|Preparation method||Exposing cells to various concentrations of Lapatinib for 72 hours. Using methylene blue stainingto estimate relative cell number . The absorbance at 620 nm is read in a Spectra microplate reader. Cell death and cell cycle analysis are assessed by propidium iodide staining and antibody detection of incorporated BrdUrd and staining with propidium iodide.|
|Concentrations||Dissolved in DMSO, final concentrations ~100 μM|
|Incubation time||72 hours|
|Animal models||CD-1 nude female mice implanted s.c. with HN5 cells, and C.B-17 SCID female mice implanted s.c. with BT474 cells|
|Formulation||Formulated in a vehicle of sulfo-butyl-ether-β-cyclodextrin 10% aqueous solution (CD10)|
|Administration||Orally twice daily|
|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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
|Solubility||DMSO 60 mg/mL|
 Binghe Xu, et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial
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