Inhibition of cyclooxygenase-2 by celecoxib reverses tumor-induced wasting
Inhibition of cyclooxygenase-2 by celecoxib reverses tumor-induced wasting
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DOI：
10.1124/jpet.103.063099
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发表时间：
2004-03-01
影响因子：
3.5
通讯作者：
Masferrer, JL
中科院分区：
文献类型：
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作者：
Davis, TW;Zweifel, BS;Masferrer, JL
有许多报道表明，抑制前列腺素的产生可能会影响肿瘤介导的消耗和相关体液因子（如高钙血症）的水平。这些减少是通过使用传统的非甾体抗炎药（NSAIDs）实现的，这通常是癌症患者的禁忌。在化疗方案中尤其如此，因为担心胃肠道出血和与内源性环氧化酶COX-1抑制相关的造血毒性。在这里，我们报道，塞来昔布，一类新的选择性COX-2抑制剂，有可能逆转肿瘤介导的消耗和相关的体液因子，如白细胞介素(IL)-6和高钙血症的恶病质的临床前模型。晚期恶病质的荷瘤小鼠在塞来昔布治疗开始的几天内体重恢复。测试了两个模型。第一个是结肠26 （Col26）同基因小鼠模型，该模型诱导高水平的循环IL-6和高钙血症。第二种是人头颈部1483 HNSCC异种移植模型，与Col26相比，它的炎症和前列腺素分泌较少。尽管在研究过程中观察到在对照药和塞来昔布治疗的动物之间没有观察到对肿瘤生长的显著影响，但塞来昔布在两种病毒质模型中迅速逆转了体重减轻。与传统非甾体抗炎药相比，塞来昔布的安全性更高，这些结果表明，塞来昔布可能用于治疗肿瘤介导的消瘦。
There have been a number of reports suggesting inhibition of prostaglandin production may impact tumor-mediated wasting and levels of associated humoral factors such as hypercalcemia. These reductions were achieved using traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which are often contraindicated in cancer patients. This is especially true during chemotherapeutic regimens due to concerns of bleeding from gastrointestinal and hematopoietic toxicities associated with inhibition of the housekeeping cyclooxygenase enzyme COX-1. Here, we report that celecoxib, one of the new class of selective COX-2 inhibitors, has the potential to reverse tumor-mediated wasting and associated humoral factors such as interleukin (IL)-6 and hypercalcemia in preclinical models of cachexia. Tumor bearing mice in late stage cachexia regained weight within days of the start of celecoxib treatment. Two models were tested. The first was the Colon 26 (Col26) syngeneic murine model that induces high levels of circulating IL-6 and hypercalcemia. The second was the human head and neck 1483 HNSCC xenograft model, which is less inflammatory and produces less prostaglandin than Col26. Despite the observation that no significant impact on tumor growth was observed between vehicle and celecoxib-treated animals over the course of the studies, celecoxib rapidly reversed weight loss in both cachectic models. With the added safety of celecoxib over traditional NSAIDs, these results suggest a possible therapeutic use for celecoxib for treating tumor-mediated wasting.