Inhibition of p53 response in tumor stroma improves efficacy of anticancer treatment by increasing antiangiogenic effects of chemotherapy and radiotherapy in mice
Inhibition of p53 response in tumor stroma improves efficacy of anticancer treatment by increasing antiangiogenic effects of chemotherapy and radiotherapy in mice
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DOI：
10.1158/0008-5472.can-06-1223
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Gudkov, Andrei V.
中科院分区：
文献类型：
--
作者：
Burdelya, Lyudmila G.;Komarova, Elena A.;Gudkov, Andrei V.
p53功能的失活，这经常发生在肿瘤中，可以显着调节肿瘤细胞对放射和化疗药物的敏感性。然而，除了作用于恶性细胞之外，抗癌剂还作用于肿瘤基质细胞，引起p53应答的激活。这种反应对治疗结果的影响一直是本研究的主题。使用产生p53抑制性逆转录病毒（编码显性阴性p53突变体）的小鼠致瘤包装细胞产生具有p53缺陷基质的肿瘤。在其基质中保持野生型p53的肿瘤由相似来源的细胞形成，但由于逆转录病毒载体中包装信号的缺失而导致逆转录病毒产生缺陷。这些肿瘤模型的比较，不同的只是在他们的基质的p53状态，显示与p53缺陷的基质的肿瘤显着更敏感的实验化疗和放疗。当抗癌治疗与p53的药理学抑制相结合时，通过pifithrin α（一种p53的小分子抑制剂）的环状形式实现了类似的效果。肿瘤间质中p53抑制增强化疗和放疗的抗癌作用可能是由于p53缺陷内皮细胞对基因毒性应激的敏感性增加，如细胞培养和实验肿瘤中所示。因此，可逆的药理学抑制p53可能是一种可行的方法，以改善抗癌治疗，通过增强抗血管生成作用的化疗和放疗。
Inactivation of p53 function, which frequently occurs in tumors, can significantly modulate tumor cell sensitivity to radiation and chemotherapeutic drugs. However, in addition to acting on malignant cells, anticancer agents act on the cells of tumor stroma, causing activation of a p53 response. The effect of this response on treatment outcome has been the subject of the present study. Tumors with p53-deficient stroma were generated using mouse tumorigenic packaging cells that produce a p53 inhibitory retrovirus, encoding a dominant-negative p53 mutant. Tumors maintaining wild-type p53 in their stroma were formed by cells of similar origin but deficient in retroviral production due to the deletion of the packaging signal in the retroviral vector. Comparison of these tumor models, differing only in p53 status of their stromas, showed that tumors with p53-deficient stroma were significantly more sensitive to experimental chemotherapy and radiotherapy. A similar effect was achieved when anticancer treatment was combined with pharmacologic suppression of p53 by the cyclic form of pifithrin alpha, a small-molecule inhibitor of p53. Potentiation of the anticancer effect of chemotherapy and radiotherapy by p53 suppression in the tumor stroma is likely to be due to the increased sensitivity of p53-deficient endothelium to genotoxic stress as shown both in cell culture and in experimental tumors. Thus, reversible pharmacologic suppression of p53 may be a viable approach to improving anticancer treatment via an enhanced antiangiogenic effect of chemotherapy and radiotherapy.