Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model.
Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model.
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发表时间：
2003
期刊：
影响因子：
11.2
通讯作者：
F. Sun;A. Tohgo;M. Bouvet;S. Yagi;Rounak Nassirpour;A. Moossa;R. Hoffman
中科院分区：
文献类型：
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作者：
F. Sun;A. Tohgo;M. Bouvet;S. Yagi;Rounak Nassirpour;A. Moossa;R. Hoffman
我们确定了喜树碱类似物DX-8951 f在胰腺癌原位转移小鼠模型中的抗肿瘤和抗转移功效。DX-8951 f在该模型中显示出对两种人胰腺肿瘤细胞系的功效。这些细胞系用绿色荧光蛋白转导，使得能够在体内高分辨率可视化肿瘤和转移生长。DX-8951 f研究包括早期和晚期癌症模型。在早期模型中，使用人胰腺癌细胞系MIA-PaCa-2和BxPC-3，当原位原发性肿瘤直径约为7 mm时开始治疗。DX-8951 f对MIA-PaCa-2和BxPC-3均显著有效。相比之下，胰腺癌的标准治疗2 '，2'-二氟脱氧胞苷（吉西他滨）对MIA-PaCa-2没有显著的功效。虽然吉西他滨对BxPC-3原发性肿瘤生长显示出显著的活性，但对转移无效。在晚期疾病模型中，使用BxPC-3，当原位原发性肿瘤直径为13 mm时开始治疗。DX-8951 f对BxPC-3原发性肿瘤以剂量-反应方式显著有效。DX-8951 f在晚期模型中也表现出抗转移活性，显著降低淋巴结转移的发生率，同时消除肺转移。相比之下，吉西他滨对原发性肿瘤仅中度有效，对晚期模型中两个部位的转移无效。因此，DX-8951 f对这种非常难以治疗的疾病的原发性和转移性生长非常有效，并且显示出比吉西他滨（胰腺癌的标准治疗）显著更高的疗效。因此，DX-8951 f具有重要的临床前景，并且比目前使用的喜树碱类似物CPT-11具有更多的积极特征，CPT-11需要代谢活化并且具有毒性。
We determined the antitumor and antimetastatic efficacy of the camptothecin analogue DX-8951f in an orthotopic metastatic mouse model of pancreatic cancer. DX-8951f showed efficacy against two human pancreatic tumor cell lines in this model. These cell lines were transduced with the green fluorescent protein, enabling high-resolution visualization of tumor and metastatic growth in vivo. The DX-8951f studies included both an early and advanced cancer model. In the early model, using the human pancreatic cancer lines MIA-PaCa-2 and BxPC-3, treatment began when the orthotopic primary tumor was approximately 7 mm in diameter. DX-8951f was significantly effective against both MIA-PaCa-2 and BxPC-3. In contrast, 2', 2'-difluorodeoxycytidine (gemcitabine), the standard treatment for pancreatic cancer, did not have significant efficacy against MIA-PaCa-2. Although gemcitabine showed significant activity against BxPC-3 primary tumor growth, it was not effective on metastasis. In the model of advanced disease, using BxPC-3, treatment started when the orthotopic primary tumor was 13 mm in diameter. DX-8951f was significantly effective in a dose-response manner on the BxPC-3 primary tumor. DX-8951f also demonstrated antimetastatic activity in the late-stage model, significantly reducing the incidence of lymph node metastasis while eliminating lung metastasis. In contrast, gemcitabine was only moderately effective against the primary tumor and ineffective against metastasis at both sites in the late-stage model. Therefore, DX-8951f was highly effective against primary and metastatic growth in this very difficult-to-treat disease and showed significantly higher efficacy than gemcitabine, the standard treatment of pancreatic cancer. DX-8951f, therefore, has important clinical promise and has more positive features than the currently used camptothecin analogue CPT-11, which requires metabolic activation and is toxic.