生物活性

Lapatinib ditosylate is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM, respectively. ErbB-2 and EGFR dual tyrosine kinases are growth promoting factors that are over expressed in some breast cancer cell lines. Research studies have reported that Lapatinib Ditosylate can inhibit breast cancer cell proliferation.

Enzymeinhibition[1]

Theantiproliferative activity of Lapatinib in breast cancer cell lines[2]

Theantiproliferative activity of lapatinib in 16 HNSCC cell lines[3]

体外研究

体内研究

2% DMSO+30% PEG 300+ddH2O

激酶实验

InVitro Kinase Assays[1]

The intracellular kinase domains of EGFR,ErbB-2, and ErbB4 were purified from a baculovirus expression system. EGFR,ErbB-2, and ErbB-4 reactions were performed in 96-well polystyreneround-bottomed plates in a final volume of 45μl. Reactionmixtures contained 50mM 4-morpholinepropanesulfonic acid (pH 7.5), 2mM MnCl2,10μM ATP, 1μCi of [γ-33P] ATP/reaction,50μM Peptide A [Biotin-(amino hexonoic acid)-EEEEYFELVAKKKCONH2; QualityControlled Biochemicals, Inc.], 1 mM dithiothreitol, and 1μl of DMSOcontaining serial dilutions of GW2016 beginning at 10μM. The reactionwas initiated by adding the indicated purified type-1 receptor intracellular domain.The amount of enzyme added was 1pmol/reaction (20 nM). Reactions wereterminated after 10 min at 23°C by adding 45μl of 0.5%phosphoric acid in water. The terminated reaction mix (75μl) wastransferred to phosphocellulose filter plates (Millipore, Marlborough, MA). Theplates were filtered and washed three times with 200μl of 0.5% phosphoricacid. Scintillation cocktail (50μl, Optiphase; Wallac) was addedto each well, and the assay was quantified by counting in a Packard Topcount.

细胞实验

Cellculture[4]

All cells were maintained in Roswell ParkMemorial Institute medium 1640 (RPMI-1640 medium) or Dulbecco’s modified Eaglemedium, which were supplemented with 10% fetal bovine serum and 1% non-essentialamino acids. Cells were grown for one week in a humidified incubator at 37 °Cand 5% CO2before the experiment, and planted at a density of 1000cells/well in a 96-well plate.

Responseto lapatinib

Microtetrazolium (MTT) assays wereperformed to assess the concentration of lapatinibnecessary to inhibit cellviability of 50%. Briefly, cells were treated for 48 h with differentconcentration of reagents ranging from 0.01 to 100 μM. Graphpad Prism softwarewas used to calculate the IC50 value which was found to be 0.75 μM forlapatinib. The infected Bladder cancer cell lines(RT112 cells ) were culturedfor 7 d and subsequently incubated with 0.75 μM lapatinib. As control, therewere 5 wells with medium only and 5 wells with 0.1% DMSO for each plate. After48 h of incubation, the presence of mini-foci was evaluated under the microscope.The relative numbers of viable cells were assessed before and after treatmentusing Celltiter Blue® Cell Viability Assay (Promega).

动物实验

In vivoantitumor activity studies[3]

Female BALB/c nu/nunude mice, 6-week old, were obtained. The mice were maintained ina laminar flow room with a constant temperature and humidity. Suspensions ofYCU-H891 cells (100 μl) (final concentration, 1x107 cells/100 μl) were injecteds.c. into the right flank of the mice on day 1. Tumor-bearing mice wererandomized (n=6) when the mean tumor volume was 50-100 mm3. Each group wasclosely matched before treatment, which began one week after celltransplantation. Lapatinib was dissolved in 0.5% hydroxypropylmethylcellulose and0.1% Tween-80 vehicle and was given once daily by oral gavage. The mice weretreated with lapatinib (50, 100, 200 mg/kg) from day 8 to day 28. The controlgroup of mice received hydroxypropylmethylcellulose/Tween-80 vehicle treatment atthe same schedule as lapatinib. Treatment group number was 8. Tumor diametersin the control and treated groups were measured weekly with a Vernier caliper.Tumor volume (V) was determined by the equation: V=ab2/2 (a, length; b, width).

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] David W. Rusnak KL, Karen Affleck. The Effects of the Novel, Reversible Epidermal Growth Factor Receptor/ErbB-2 Tyrosine Kinase Inhibitor, GW2016, on the Growth of Human Normal and Tumor-derived Cell Lines in Vitro and in Vivo. Molecular Cancer Therapeutics. 2001;1(2):85-94.
[2] Hegde PS, Rusnak D, Bertiaux M, et al. Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles. Mol Cancer Ther. 2007;6(5):1629-1640.
[more]

体内溶解度
10mg/mL

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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