The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice.
The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice.
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APO2L/TRAIL对SCID小鼠中异种移植物的胰腺腺癌患者胰腺腺癌的抗肿瘤作用。
DOI：
10.1186/1479-5876-3-22
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发表时间：
2005-05-19
影响因子：
7.4
通讯作者：
Repasky, EA
中科院分区：
文献类型：
--
作者：
Hylander, BL;Pitoniak, R;Penetrante, RB;Gibbs, JF;Oktay, D;Cheng, JR;Repasky, EA
Apo 2L/TRAIL在癌症治疗中具有相当大的前景，这是基于肿瘤坏死因子家族的这一成员在大多数恶性细胞中诱导凋亡，而正常细胞更具抗性的事实。此外，在许多细胞中，当Apo 2L/TRAIL与化疗组合时，效果是协同的。这项工作的大部分是使用细胞系进行的。因此，研究患者肿瘤对Apo 2L/TRAIL的反应可以验证和/或补充从细胞系获得的信息，并证明在未来临床试验的设计中有价值。我们已经使用患者肿瘤异种移植物/ SCID小鼠模型研究了患者来源的胰腺肿瘤的Apo 2L/TRAIL敏感性。用Apo 2L/TRAIL、吉西他滨或两种疗法的组合治疗携带移植肿瘤的小鼠。作为异种移植物生长的患者肿瘤表现出对Apo 2L/TRAIL的一系列敏感性。发现了Apo 2L/TRAIL敏感性和耐药性胰腺肿瘤，以及表现出反应异质性的肿瘤。通过Western印迹分析Apo 2L/TRAIL处理后敏感肿瘤中凋亡信号分子的变化;观察到半胱氨酸天冬氨酸蛋白酶原8、Bid和半胱氨酸天冬氨酸蛋白酶原3的丢失，并与肿瘤生长的抑制相关。然而，在对Apo 2L/TRAIL的杀伤具有高度抗性的肿瘤中，尽管响应于Apo 2L/TRAIL处理存在半胱天冬酶原8和Bid的部分损失，但半胱天冬酶原3的损失可忽略不计。这种耐药肿瘤还表达高水平的抗凋亡分子Bcl-XL，相比之下，在敏感肿瘤中未检测到。重要的是，在大多数这些肿瘤中，将吉西他滨添加到Apo 2L/TRAIL中导致比单独使用任一种疗法更大的抗肿瘤作用。这些数据表明，在临床环境中，我们将看到患者肿瘤对Apo 2L/TRAIL的反应的异质性，包括高度敏感的肿瘤以及耐药的肿瘤。虽然需要更多的工作来理解这种异质性的分子基础，但令人鼓舞的是，Apo 2L/TRAIL与吉西他滨组合几乎在每种情况下都增加了治疗功效，因此可能是一种非常有效的控制人胰腺癌的策略，验证和扩展了细胞系的报道。
Apo2L/TRAIL has considerable promise for cancer therapy based on the fact that this member of the tumor necrosis factor family induces apoptosis in the majority of malignant cells, while normal cells are more resistant. Furthermore, in many cells, when Apo2L/TRAIL is combined with chemotherapy, the effect is synergistic. The majority of this work has been carried out using cell lines. Therefore, investigation of how patient tumors respond to Apo2L/TRAIL can validate and/or complement information obtained from cell lines and prove valuable in the design of future clinical trials. We have investigated the Apo2L/TRAIL sensitivity of patient derived pancreatic tumors using a patient tumor xenograft/ SCID mouse model. Mice bearing engrafted tumors were treated with Apo2L/TRAIL, gemcitabine or a combination of both therapies. Patient tumors grown as xenografts exhibited a spectrum of sensitivity to Apo2L/TRAIL. Both Apo2L/TRAIL sensitive and resistant pancreatic tumors were found, as well as tumors that showed heterogeneity of response. Changes in apoptotic signaling molecules in a sensitive tumor were analyzed by Western blot following Apo2L/TRAIL treatment; loss of procaspase 8, Bid and procaspase 3 was observed and correlated with inhibition of tumor growth. However, in a tumor that was highly resistant to killing by Apo2L/TRAIL, although there was a partial loss of procaspase 8 and Bid in response to Apo2L/TRAIL treatment, loss of procaspase 3 was negligible. This resistant tumor also expressed a high level of the anti-apoptotic molecule Bcl-XL that, in comparison, was not detected in a sensitive tumor. Importantly, in the majority of these tumors, addition of gemcitabine to Apo2L/TRAIL resulted in a greater anti-tumor effect than either therapy used alone. These data suggest that in a clinical setting we will see heterogeneity in the response of patients' tumors to Apo2L/TRAIL, including tumors that are highly sensitive as well as those that are resistant. While much more work is needed to understand the molecular basis for this heterogeneity, it is very encouraging, that Apo2L/TRAIL in combination with gemcitabine increased therapeutic efficacy in almost every case and therefore may be a highly effective strategy for controlling human pancreatic cancer validating and expanding upon what has been reported for cell lines.
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影响因子：
11.2
作者：
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通讯作者：
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通讯作者：
Schmid, RA