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极光 B 激酶抑制剂 AZD1152：作用决定因素及增强胰腺癌和结肠癌化疗效果的能力。

Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer.

机构信息

Clinical Experimental Oncology Laboratory, National Cancer Institute, Via Hahnemann 10, Bari 70126, Italy.

出版信息

Br J Cancer. 2011 Mar 1;104(5):769-80. doi: 10.1038/bjc.2011.21. Epub 2011 Feb 8.

DOI:10.1038/bjc.2011.21
PMID:21304529
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3048212/
Abstract

BACKGROUND

AZD1152, the prodrug for AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a selective inhibitor of Aurora B kinase activity. Preclinical evaluation of AZD1152 has been reported in several human cancer models. The potentiality of this compound in combination therapy warrants further investigation in solid tumours.

EXPERIMENTAL DESIGN

This study explored the effects of AZD1152-HQPA in colon and pancreatic tumour cells. The antitumour properties of AZD1152, either as single agent or in combination with chemotherapeutics, were evaluated in each study model. The efficacy and the toxicity of AZD1152 alone and in combination with gemcitabine were validated in pancreatic tumour xenograft model.

RESULTS

AZD1152-HQPA treatment resulted in a dramatic increase of chromosome number, modification of cell cycle and induction of apoptosis. The most effective combination was that with chemotherapeutics given soon after AZD1152 in both tumour cell types. The effectiveness of the sequential schedule of AZD1152 with gemcitabine was confirmed in nude mice bearing MiaPaCa-2 tumours, showing inhibition of tumour volumes and delaying of tumour growth after the interruption of the treatments. Here we show that AZD1152-HQPA enhances oxaliplatin and gemcitabine effectiveness in colon and pancreatic cancer, respectively. First, we provide advances into administration schedules and dosing regimens for the combination treatment in in vivo pancreatic tumour.

摘要

背景

AZD1152 是 Aurora B 激酶活性的选择性抑制剂，是 AZD1152-羟基喹啉吡唑苯胺（HQPA）的前药。在几种人类癌症模型中已经报道了 AZD1152 的临床前评估。该化合物在联合治疗中的潜力值得在实体瘤中进一步研究。

实验设计

本研究探讨了 AZD1152-HQPA 在结肠和胰腺肿瘤细胞中的作用。在每个研究模型中，评估了 AZD1152 作为单一药物或与化疗药物联合使用的抗肿瘤特性。在胰腺肿瘤异种移植模型中验证了 AZD1152 单独使用和与吉西他滨联合使用的疗效和毒性。

结果

AZD1152-HQPA 治疗导致染色体数量急剧增加、细胞周期改变和细胞凋亡诱导。在两种肿瘤细胞类型中，AZD1152 后不久给予化疗药物的联合治疗最为有效。在携带 MiaPaCa-2 肿瘤的裸鼠中，AZD1152 与吉西他滨的序贯方案的有效性得到了证实，显示出肿瘤体积的抑制和治疗中断后肿瘤生长的延迟。在这里，我们表明 AZD1152-HQPA 增强了奥沙利铂和吉西他滨在结肠癌和胰腺癌中的有效性。首先，我们为体内胰腺癌的联合治疗提供了给药方案和剂量方案的进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/1b92c6ce3544/bjc201121f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/cce7c31db4ff/bjc201121f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/9dea16797410/bjc201121f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/89772e4f03fd/bjc201121f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/3ffb23f531f0/bjc201121f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/3e80c04296a5/bjc201121f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/1b92c6ce3544/bjc201121f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/cce7c31db4ff/bjc201121f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/9dea16797410/bjc201121f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/89772e4f03fd/bjc201121f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/3ffb23f531f0/bjc201121f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/3e80c04296a5/bjc201121f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5eac/3048212/1b92c6ce3544/bjc201121f6.jpg

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