2012年8月16日 讯 /生物谷BIOON/ --比利时鲁汶大学研究人员证实了他们的假设：通过阻断氧气传感分子(oxygen sensor)PHD2让血管恢复正常能够让化疗更加有效。他们也第一次证实这种策略能够降低化疗给健康器官带来的副作用。
化疗的有效性因人们很难运送抗癌药物到肿瘤中而受到较大限制。肿瘤的特征在于血管形状异常：它们的形状不规则，质地松软而且容易撕裂。这些有漏洞的血管阻止抗癌药物到达肿瘤细胞，同时促进癌症转移。另外，化疗能够对健康器官带来严重的副作用，甚至会导致心脏和肾脏功能衰竭。
Max Mazzone实验室早期的研究已证实在低氧环境下降低氧气传感分子PHD2的活性导致更加正常的血管系统。在这项新研究中，利用小鼠模式动物，研究员Rodrigo Leite de Oliveira、Sofie Deschoemaker和Max Mazzone证实他们早期的假设：通过抑制PHD2让血液流动正常化能够让癌症治疗更加有效。首先，更好形成的血管确保抗癌药物在整个肿瘤内分布，从而增加它们的疗效。它们也允许人们服用更小剂量的药物，对有毒药物而言，这是一个显著性的优势。研究人员进一步证实抑制PHD2导致能够中和化疗副作用的抗氧化剂酶的产生。
这项研究是大有希望的：结合特异性PHD2抑制剂的化疗将使得化疗更加有效，同时降低副作用。不幸的是，就目前而言，还没有特异性的PHD2抑制剂供人们使用，因此在开发出有效的药物之前，研究人员还有一段很长的路要走。(生物谷Bioon.com)
本文编译自Scientists Uncover Strategy Able to Dramatically Reduce Chemotherapy’s Side Effects
doi: 10.1016/j.ccr.2012.06.028
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Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity
Rodrigo Leite de Oliveira, Sofie Deschoemaeker, Anne-Theres Henze, Koen Debackere, Veronica Finisguerra, Yukiji Takeda, Carmen Roncal, Daniela Dettori, Evelyne Tack, Yannick Jönsson, Lorenzo Veschini, Annelies Peeters, Andrey Anisimov, Matthias Hofmann, Kari Alitalo, Myriam Baes, Jan D'hooge, Peter Carmeliet, Massimiliano Mazzone
The success of chemotherapy in cancer treatment is limited by scarce drug delivery to the tumor and severe side-toxicity. Prolyl hydroxylase domain protein 2 (PHD2) is an oxygen/redox-sensitive enzyme that induces cellular adaptations to stress conditions. Reduced activity of PHD2 in endothelial cells normalizes tumor vessels and enhances perfusion. Here, we show that tumor vessel normalization by genetic inactivation of Phd2 increases the delivery of chemotherapeutics to the tumor and, hence, their antitumor and antimetastatic effect, regardless of combined inhibition of Phd2 in cancer cells. In response to chemotherapy-induced oxidative stress, pharmacological inhibition or genetic inactivation of Phd2 enhances a hypoxia-inducible transcription factor (HIF)-mediated detoxification program in healthy organs, which prevents oxidative damage, organ failure, and tissue demise. Altogether, our study discloses alternative strategies for chemotherapy optimization.
