2012年8月16日 訊 /生物谷BIOON/ --比利時(shí)魯汶大學(xué)研究人員證實(shí)了他們的假設(shè)：通過阻斷氧氣傳感分子(oxygen sensor)PHD2讓血管恢復(fù)正常能夠讓化療更加有效,。他們也第一次證實(shí)這種策略能夠降低化療給健康器官帶來的副作用,。
化療的有效性因人們很難運(yùn)送抗癌藥物到腫瘤中而受到較大限制。腫瘤的特征在于血管形狀異常：它們的形狀不規(guī)則,，質(zhì)地松軟而且容易撕裂,。這些有漏洞的血管阻止抗癌藥物到達(dá)腫瘤細(xì)胞，同時(shí)促進(jìn)癌癥轉(zhuǎn)移,。另外,，化療能夠?qū)】灯鞴賻韲?yán)重的副作用，甚至?xí)?dǎo)致心臟和腎臟功能衰竭,。
Max Mazzone實(shí)驗(yàn)室早期的研究已證實(shí)在低氧環(huán)境下降低氧氣傳感分子PHD2的活性導(dǎo)致更加正常的血管系統(tǒng),。在這項(xiàng)新研究中，利用小鼠模式動(dòng)物,，研究員Rodrigo Leite de Oliveira,、Sofie Deschoemaker和Max Mazzone證實(shí)他們?cè)缙诘募僭O(shè)：通過抑制PHD2讓血液流動(dòng)正常化能夠讓癌癥治療更加有效,。首先,，更好形成的血管確保抗癌藥物在整個(gè)腫瘤內(nèi)分布,，從而增加它們的療效,。它們也允許人們服用更小劑量的藥物，對(duì)有毒藥物而言,，這是一個(gè)顯著性的優(yōu)勢(shì),。研究人員進(jìn)一步證實(shí)抑制PHD2導(dǎo)致能夠中和化療副作用的抗氧化劑酶的產(chǎn)生。
這項(xiàng)研究是大有希望的：結(jié)合特異性PHD2抑制劑的化療將使得化療更加有效,，同時(shí)降低副作用,。不幸的是,，就目前而言，還沒有特異性的PHD2抑制劑供人們使用,，因此在開發(fā)出有效的藥物之前,，研究人員還有一段很長的路要走。(生物谷Bioon.com)
本文編譯自Scientists Uncover Strategy Able to Dramatically Reduce Chemotherapy’s Side Effects
doi: 10.1016/j.ccr.2012.06.028
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PMID:
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.
