2012年8月16日 訊 /生物谷BIOON/ --比利時魯汶大學研究人員證實了他們的假設：通過阻斷氧氣傳感分子(oxygen sensor)PHD2讓血管恢復正常能夠讓化療更加有效。他們也第一次證實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腫瘤細胞,，同時促進癌癥轉移。另外,，化療能夠對健康器官帶來嚴重的副作用,，甚至會導致心臟和腎臟功能衰竭。
Max Mazzone實驗室早期的研究已證實在低氧環(huán)境下降低氧氣傳感分子PHD2的活性導致更加正常的血管系統(tǒng),。在這項新研究中,，利用小鼠模式動物，研究員Rodrigo Leite de Oliveira,、Sofie Deschoemaker和Max Mazzone證實他們早期的假設：通過抑制PHD2讓血液流動正?；軌蜃尠┌Y治療更加有效。首先,，更好形成的血管確?？拱┧幬镌谡麄€腫瘤內分布，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,，對有毒藥物而言，這是一個顯著性的優(yōu)勢,。研究人員進一步證實抑制PHD2導致能夠中和化療副作用的抗氧化劑酶的產生,。
這項研究是大有希望的：結合特異性PHD2抑制劑的化療將使得化療更加有效，同時降低副作用,。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
PMC:
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.
