生物谷：美国德州大学西南医学院的研究人员发表于10月版的Cancer Research杂志的研究报告称将药物BEZ235和低剂量辐射(low-dose radiation)结合能够阻断PI3K蛋白的活性。研究人员将这种新的治疗方法应用到移植人类非小细胞肺癌(non-small cell lung cancer, NSCL)的老鼠上，发现用BEZ235药物治疗过的小鼠和未用药治疗的老鼠相比，前者的肿瘤出现明显缩小。而将BEZ235与放射性治疗相结合，发现这种方法可以使肿瘤完全消失。
NSCL癌细胞内在K-RAS基因上携带多个突变，而K-RAS突变体能够激活调节肿瘤生长的信号蛋白(signaling proteins),PI3K即为其中一种蛋白，PI3K蛋白可修复肿瘤细胞的DNA损伤。因此研究人员认为PI3K可作为一种潜在的抗癌药物及靶标。目前，临床试验中所使用的药物BEZ235就是以PI3K和另一种信号蛋白mTOR为肿瘤治疗靶标。
在开始测试BEZ235单独使用的有效性实验中，研究人员发现该药物不但能够抑制活体培养肺癌细胞的增殖，还能抑制患肺癌老鼠的肿瘤生长。
随后，研究人员将经BEZ235处理过的癌细胞置于低剂量辐射中，这种低剂量辐射只会使细胞内DNA出现断裂但不会影响细胞生存，当DNA出现损伤后，癌细胞可通过PI3K信号通路进行修复。研究人员发现，当BEZ235阻断PI3K信号蛋白，MSCL肿瘤细胞逐渐凋亡。
研究人员称，该实验的下一步将是在临床上利用BEZ235或类似药物治疗NSCL肿瘤患者。（生物谷Bioon.com）
更多放射加药物癌症治疗研究：
Cancer Research：改善肿瘤中血管状况有助于癌症放疗
JAMA：切除术后放射疗法可增前列腺癌患者存活率
Int.J.Hyp.：热疗加化疗治疗癌症效果更好
PLoS ONE：癌症治疗新技术—放射免疫治疗
生物谷推荐原始出处：
Cancer Research 69, 7644, October 1, 2009.doi: 10.1158/0008-5472.CAN-09-0823
Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Blockade Is an Effective Radiosensitizing Strategy for the Treatment of Non–Small Cell Lung Cancer Harboring K-RAS Mutations
Georgia Konstantinidou1,4, Erik A. Bey2, Andrea Rabellino1, Katja Schuster1, Michael S. Maira5, Adi F. Gazdar3, Augusto Amici4, David A. Boothman2 and Pier Paolo Scaglioni1
1 Division of Hematology and Oncology, 2 Simmons Comprehensive Cancer Center, and 3 Hamon Center for Therapeutic Oncology Research, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; 4 Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy; and 5 Novartis Institutes for Biomedical Research, Oncology Disease Area, Novartis Pharma AG, Basel, Switzerland
Requests for reprints: Pier Paolo Scaglioni, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, ND3120A, Dallas, TX 75390.
Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC often harbors oncogenic K-RAS mutations that lead to the aberrant activation of several intracellular networks including the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Oncogenic K-RAS predicts poor prognosis and resistance to treatment with ionizing radiation (IR). Oncogenic K-Ras expression in the respiratory epithelium is sufficient to initiate NSCLC tumorigenesis, which requires the catalytic subunit of PI3K. Thus, effective inhibition of the PI3K signaling should lead to significant antitumor effects. However, therapy with rapamycin analogues has yielded disappointing results due in part to compensatory up-regulation of AKT. We hypothesized that dual PI3K/mTOR blockade would overcome these limitations. We tested this hypothesis with BEZ235, a novel dual PI3K/mTOR inhibitor that has recently entered clinical development. We found that BEZ235 induces a striking antiproliferative effect both in transgenic mice with oncogenic K-RAS–induced NSCLC and in NSCLC cell lines expressing oncogenic K-RAS. We determined that treatment with BEZ235 was not sufficient to induce apoptosis. However, we found that dual PI3K/mTOR blockade effectively sensitizes NSCLC expressing oncogenic K-RAS to the proapoptotic effects of IR both in vitro and in vivo. We conclude that dual PI3K/mTOR blockade in combination with IR may benefit patients with NSCLC expressing oncogenic K-RAS. These findings may have general applicability in cancer therapy, because aberrant activation of PI3K occurs frequently in human cancer.
