Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma.
Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma.
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DOI：
10.1158/1535-7163.mct-08-0370
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发表时间：
2008-09
影响因子：
5.7
通讯作者：
Gustafson DL
中科院分区：
文献类型：
--
作者：
Bradshaw-Pierce EL;Steinhauer CA;Raben D;Gustafson DL
多西紫杉醇（DTX）通常根据最大耐受剂量（MTD）给药，可以在低nM浓度下抑制内皮细胞（EC）的增殖。DTX可能发挥抗血管生成作用，如果给药，使血浆水平在较长时间内维持在低纳米浓度。在头颈部异种移植模型中，我们评估了DTX加vandetanib（一种具有抗血管生成和抗肿瘤活性的VEGFR-2和EGFR酪氨酸激酶抑制剂）和不加vandetanib的节律和mtd剂量。修改了基于小鼠生理的药代动力学模型，以预测腹腔内给药后DTX的分布，以设计针对预先指定的血浆浓度的给药方案，用于抗内皮效应（节律）或暴露，模拟人类30mg/m2（每周/MTD） DTX。动物在携带UMSCC2肿瘤异种移植的小鼠中分别给予1mg/kg/天（DTX1）或6mg/kg q4d (DTX6) DTX加或不加VAN （15mg /kg/天p.o）治疗28天。DTX1给药方案调整为治疗10天，然后由于严重的胃肠道毒性而休息9天。与对照组相比，各治疗组均显著降低肿瘤体积、肿瘤增殖（Ki-67）和肿瘤EC增殖（Ki-67/vonWillebrand因子）。与单一药物治疗相比，在DTX治疗中加入VAN显著增强了肿瘤生长抑制。肿瘤EC增殖与肿瘤生长速率正相关，表明VAN和DTX具有抗血管生成作用。由于DTX1治疗中观察到的发病率，很难明确确定节拍法是否对治疗有效。DTX与VAN在治疗UMSCC2异种移植物中是有效的浓度与暴露在人类。
Docetaxel (DTX), usually administered according to maximum tolerated dosing (MTD), can inhibit endothelial cell (EC) proliferation at low nM concentrations. DTX may exert antiangiogenic effects if dosed so plasma levels are maintained at low nM concentrations over a prolonged time. We evaluated metronomic and MTD-based dosing of DTX with and without vandetanib (VAN), a VEGFR-2 and EGFR tyrosine kinase inhibitor with antiangiogenic and anti-tumor activity, in a head and neck xenograft model. A murine physiologically-based pharmacokinetic model was modified to predict DTX distribution following intraperitoneal administration to design dosing regimens that target pre-specified plasma concentrations, for anti-endothelial effects (metronomic), or exposure, to mimic 30mg/m2 (weekly/MTD) DTX in humans. Animals were treated for 28 days with 1mg/kg/day (DTX1) or 6mg/kg q4d (DTX6) DTX with or without VAN (15 mg/kg/day p.o.) in mice bearing UMSCC2 tumor xenografts. The DTX1 dosing scheme was adjusted to treatment for 10 days followed by 9 days off due to severe GI toxicity. All treatment groups significantly reduced tumor volume, tumor proliferation (Ki-67) and tumor EC proliferation (Ki-67/vonWillebrand factor) compared with control. Addition of VAN to DTX treatment significantly enhanced tumor growth inhibition over single agent therapy. A positive correlation of tumor EC proliferation with tumor growth rates demonstrates VAN and DTX antiangiogenic effects. Due to the morbidity observed with DTX1 treatment it is difficult to clearly ascertain if metronomic schedules will be effective for treatment. DTX with VAN is effective in treating UMSCC2 xenografts at concentrations relevant to exposures in humans.