5月9日，一項(xiàng)刊登在國際雜志Science Translational Medicine上的研究報(bào)告說,，基因療法可能有助于保護(hù)腦癌患者免受化療的有害影響,。該策略應(yīng)能使患者接受更高且更有效的化療劑量——但不會增加像血細(xì)胞計(jì)數(shù)低下這樣的危險(xiǎn)并發(fā)癥的風(fēng)險(xiǎn)。血細(xì)胞下降會開啟感染,、過度出血及其它疾病之門,，這些情況會迫使許多病人停止治療直到細(xì)胞計(jì)數(shù)得到改善,。
不幸的是，間歇性地停止治療會給癌癥一個擴(kuò)散的機(jī)會并會令其對化療產(chǎn)生抗藥性,。腦癌細(xì)胞會大量產(chǎn)出一種叫做MGMT的蛋白,，該蛋白會令腦癌細(xì)胞對化療具有抗藥性，因此醫(yī)生會用第二種叫做芐基鳥嘌呤的藥物來遏制MGMT并使腫瘤細(xì)胞對化療變的重新敏感,。不幸的是,，正常的血細(xì)胞和骨髓細(xì)胞（它們無法制造MGMT）無法承受芐基鳥嘌呤與化療的組合，因此治療常常以損害健康細(xì)胞而告終,。
Jennifer Adair及其同事設(shè)計(jì)了一種避開這一問題的方法,，即在一小群的腦癌患者中對骨髓干細(xì)胞進(jìn)行基因改良。這些病人罹患對化療有抵抗力的腦腫瘤,，其存活機(jī)會非常差,。研究人員在病人的骨髓干細(xì)胞中嵌入了一個叫做PK140的保護(hù)性基因,。PK140是設(shè)計(jì)用來防護(hù)細(xì)胞免受像替莫唑胺這樣的常見化療藥物的損害,。在骨髓移植之后，患者被給予了更高劑量的化療,。與那些接受同樣類型化療但沒有接受基因改良的骨髓干細(xì)胞移植的患者相比,，這些患者能夠在干細(xì)胞移植后更好地耐受較高的化療劑量。此外,，這些接受移植的患者比預(yù)計(jì)的時間活的更長,，而且沒有來自改變細(xì)胞的任何不良的副作用。這些結(jié)果為研發(fā)針對克服化療抗藥性并改善腦癌患者存活力的療法鋪平了道路,。（生物谷Bioon.com）
doi:10.1126/scitranslmed.3003425
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Extended Survival of Glioblastoma Patients After Chemoprotective HSC Gene Therapy
Jennifer E. Adair1,*, Brian C. Beard1,2,*, Grant D. Trobridge3, Tobias Neff4,5, Jason K. Rockhill6,7, Daniel L. Silbergeld6,8, Maciej M. Mrugala6,9 and Hans-Peter Kiem1,2,8,†
Chemotherapy with alkylating agents for treating malignant disease results in myelosuppression that can significantly limit dose escalation and potential clinical efficacy. Gene therapy using mutant methylguanine methyltransferase (P140K) gene–modified hematopoietic stem and progenitor cells may circumvent this problem by abrogating the toxic effects of chemotherapy on hematopoietic cells. However, this approach has not been evaluated clinically. Here, we show efficient polyclonal engraftment of autologous P140K-modified hematopoietic stem and progenitor cells in three patients with glioblastoma. Increases in P140K-modified cells after transplant indicate selection of gene-modified hematopoietic repopulating cells. Longitudinal retroviral integration site (RIS) analysis identified more than 12,000 unique RISs in the three glioblastoma patients, with multiple clones present in the peripheral blood of each patient throughout multiple chemotherapy cycles. To assess safety, we monitored RIS distribution over the course of chemotherapy treatments. Two patients exhibited emergence of prominent clones harboring RISs associated with the intronic coding region of PRDM16 (PR domain–containing 16) or the 3′ untranslated region of HMGA2 (high-mobility group A2) genes with no adverse clinical outcomes. All three patients surpassed the median survival for glioblastoma patients with poor prognosis, with one patient alive and progression-free more than 2 years after diagnosis. Thus, transplanted P140K-expressing hematopoietic stem and progenitor cells are chemoprotective, potentially maximizing the drug dose that can be administered.
