Xiong Henry Q, Herbst Roy, Faria Silvana C, Scholz Catherine, Davis Darren, Jackson Edward F, Madden Timothy, McConkey David, Hicks Marshall, Hess Kenneth, Charnsangavej Chusilp Arthur, Abbruzzese James L
Department of Gastrointestinal Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.
Invest New Drugs. 2004 Nov;22(4):459-66. doi: 10.1023/B:DRUG.0000036688.96453.8d.
To evaluate the biologic effects of SU6668 in patients with solid tumors using comprehensive measures of pharmacokinetics (PK), functional imaging, and tissue correlative studies.
Eligible patients with tumors accessible for core needle biopsy were treated with SU6668 at doses of 200 or 400 mg/m(2)/day. Functional computed tomography (CT) scan and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed at baseline and repeated 4 weeks and 12 weeks after treatment for analysis of tumor angiogenesis. The PK was analyzed using a high-performance liquid chromatography assay. Tumor specimens obtained via core needle biopsy at baseline and 4 weeks later were analyzed for the biologic effects of SU6668.
Six of a total of seven patients received treatment for at least 3 months and underwent comprehensive correlative studies, including PK, imaging, and tissue biopsy. Functional CT showed that five of six patients had decreased blood flow in tumors in response to treatment, and DCE-MRI results indicated significant change of area under the signal intensity vs. time curve (AUC) and/or maximum slope (maximum rate of signal intensity change) in two of four patients evaluated with this technique. PK studies showed that the mean apparent oral clearance (Cl(oral)) measured on day 1 was 6.3 +/- 2.7 L/hr/m(2), yielding a mean AUC of 16.6 +/- 4.3 mg/L.hr. By day 22, the Cl(oral) was 40% more than that observed on day 1.
It is feasible to evaluate the biologic effects of antiangiogenic agents using comprehensive surrogate measures.
采用药代动力学（PK）、功能成像及组织相关性研究等综合方法，评估SU6668对实体瘤患者的生物学效应。
符合条件且肿瘤可进行粗针活检的患者，接受剂量为200或400mg/m²/天的SU6668治疗。在基线时进行功能计算机断层扫描（CT）及动态对比增强磁共振成像（DCE-MRI），并在治疗后4周和12周重复进行，以分析肿瘤血管生成情况。采用高效液相色谱分析法分析PK。对基线时及4周后通过粗针活检获取的肿瘤标本进行分析，以研究SU6668的生物学效应。
7名患者中6名接受了至少3个月的治疗，并进行了包括PK、成像及组织活检在内的综合相关性研究。功能CT显示，6名患者中有5名治疗后肿瘤血流减少，DCE-MRI结果表明，在接受该技术评估的4名患者中，有2名患者的信号强度-时间曲线下面积（AUC）和/或最大斜率（信号强度变化的最大速率）发生了显著变化。PK研究表明，第1天测得的平均表观口服清除率（Cl(oral)）为6.3±2.7L/hr/m²，平均AUC为16.6±4.3mg/L·hr。到第22天，Cl(oral)比第1天观察到的值高40%。
使用综合替代指标评估抗血管生成药物的生物学效应是可行的。
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