Lapatinib 拉帕替尼

溶剂体积

浓度

体外研究：

细胞类型（Cell type）：EGFR-overexpressing cell lines HN5, ErbB-2-overexpressing cell lines BT474, Normal human foreskin fibroblasts (HFF)

药物配制（Preparation）：GW2016 was dissolved in DMSO

实验方法（Assay）：Cells are plated in 96-well plates in the media at the following densities: HFF and HN5, 1000 cells/well and BT474, 5000 cells/well.After 24 h, the cells are exposed to vehicle (0.3% DMSO) or Lapatinib (1 nM, 10 nM, 100 nM, 1μM, 10μM, and 100μM).Lapatinib is removed from the cells after 72 h and is replaced by either DMEM containing 10% FBS and 50 μg/mL Gentamicin (HFF and HN5) or RPMI containing 10% FBS and 50 μg/mL Gentamicin (BT474). Methylene blue staining is performed at the time points over a total period of 16 day.

体内研究：

动物模型（Animal Model）：BT474 human tumor xenografts (established in C.B-17 SCID female mice), HN5 human tumor xenografts (established in CD-1 nude female mice)

药物配制（Preparation）：GW2016 was dissolved in a vehicle of sulfo-butyl-ether-β-cyclodextrin 10% aqueous solution.

给药剂量（Dosages）：Experimental compounds (30mg/kg and 100mg/kg) were administered p.o. twice daily for 21 days in a vehicle of sulfo-butyl-ether-β-cyclodextrin 10% aqueous solution.

实验结果（Results）：GW2016 was potent at inhibiting the growth of BT474 and HN5 human tumor xenografts. A dose-responsive inhibition of both models occurred on treatment of tumor-bearing mice with 30 and 100 mg/kg GW2016 orally, twice daily. Complete inhibition of tumor growth was seen at the 100 mg/kg dose.

体外研究：

细胞类型（Cell type）：14 established human gastric and esophageal cancer cell lines that express variable levels of EGFR and HER2: AGS, NCI-N87, KATO III, SNU-1, SNU-5, and SNU-16; NUGC4, NUGC3, FU97, IM95, IM95m, MKN74, and MKN1; OE19;

药物配制（Preparation）：Lapatinib was prepared as a 10 mmol/L stock solution in DMSO.

实验方法（Assay）：Cells were plated into 24-well plates at a density of 2 × 104to 6 × 104and grown in cell line– specific medium in decreasing concentrations of both lapatinib (ranging between 10 and 0.3125 μM) and erlotinib (ranging between 10 and 0.3125 μM). The same cell lines were treated with trastuzumab at a fixed dose of 10 μg/mL. Cells were harvested by trypsinization on day 6 and counted using a particle counter.

体内研究：

动物模型（Animal Model）：N87-bearing xenografts

药物配制（Preparation）：Lapatinib was dissolved in 0.5% hydroxypropyl methylcellulose (HPMC) with 0.1% Tween 80.

注射剂量（Dosages）：N87 cells (5×106cells with 50% Matrigel) were injected s.c. into nude mice and mice were randomized into one of four groups (n = 11/group).Treatment started at day 4 after injection with either lapatinib (100 mg/kg daily for 3 wkby oral gavage in 0.5% hydroxypropyl methylcellulose and 0.1% Tween 80),trastuzumab (10 mg/kgin sterile PBS,i.p. twice weekly) or sterile PBS (i.p. twice weekly) or the combination of lapatinib and trastuzumab at the doses above. Tumors were measured biweekly. After 23 d of treatment, the animals were euthanized.

实验结果（Results）：Both single-agent lapatinib and trastuzumab caused tumor regression in N87 xenografts. In addition, the combination showed near complete tumor resolution by day 23.

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