Davis Thomas W, O'Neal Janet M, Pagel Mark D, Zweifel Ben S, Mehta Pramod P, Heuvelman Deborah M, Masferrer Jaime L
Oncology Discovery Research, Pfizer Corporation, St. Louis, Missouri 63017, USA.
Cancer Res. 2004 Jan 1;64(1):279-85. doi: 10.1158/0008-5472.can-03-1168.
Previous work has demonstrated that selective cyclooxygenase-2 (COX-2) inhibitors can act synergistically with radiotherapy to improve tumor debulking and control in preclinical models. The underlying mechanism of this remarkable activity has not yet been determined. Here, we report that radiation can elevate intratumoral levels of COX-2 protein and its products, particularly prostaglandin E(2) (PGE(2)). Furthermore, inhibition of COX-2 activity or neutralization of PGE(2) activity enhances radiotherapy even in tumors where COX-2 expression is restricted to the tumor neovasculature. Direct assessment of vascular function by direct contrast enhancement-magnetic resonance imaging showed that the combination of radiation and celecoxib lead to enhanced vascular permeability. These observations suggest that an important mechanism of celecoxib-induced radiosensitization involves inhibition of COX-2-derived PGE(2), thus removing a survival factor for the tumor and its vasculature.
先前的研究表明，在临床前模型中，选择性环氧化酶-2（COX-2）抑制剂可与放射疗法协同作用，以改善肿瘤体积缩小和控制情况。这种显著活性的潜在机制尚未确定。在此，我们报告放射可提高肿瘤内COX-2蛋白及其产物的水平，尤其是前列腺素E2（PGE2）。此外，即使在COX-2表达仅限于肿瘤新生血管的肿瘤中，抑制COX-2活性或中和PGE2活性也能增强放射治疗效果。通过直接对比增强磁共振成像对血管功能进行直接评估显示，放射治疗与塞来昔布联合使用可导致血管通透性增强。这些观察结果表明，塞来昔布诱导放射增敏的一个重要机制涉及抑制COX-2衍生的PGE2，从而消除肿瘤及其血管的一个存活因子。
