COX-2 in cancer--a player that's defining the rules.
COX-2 in cancer--a player that's defining the rules.
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癌症中的 COX-2——定义规则的参与者。
DOI：
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
R. Dubois
中科院分区：
文献类型：
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作者：
E. Hawk;J. Viner;A. Dannenberg;R. Dubois
环氧合酶（考克斯）抑制剂在广泛用于炎症、发热和疼痛世纪后正被开发为用于预防和治疗癌症的潜在药剂。从20世纪70年代末开始，研究人员注意到肿瘤病变中的阿糖胞苷浓度升高，这表明花生四烯酸代谢产物在肿瘤发生中的作用。体外、体内、观察和临床等多方面的证据证实，考克斯抑制剂可减少前列腺素的产生，降低结直肠、皮肤和其他肿瘤的风险[1]。由于传统的非选择性考克斯抑制剂的胃肠道安全性问题，已经开发了选择性靶向考克斯-2的衍生物用于关节炎、镇痛和肿瘤治疗。考克斯-2选择性抑制剂作为分子靶向、细胞生长抑制剂的范例（2）。考克斯-2在大比例和多种人类和啮齿类动物肿瘤中持续过表达（3）。通过消除（4）或诱导（5）考克斯-2表达的遗传操作，分别导致肿瘤显著缩小或刺激，证实了与体内致癌作用的致病相关性。食品和药物管理局（FDA）批准的选择性考克斯-2抑制剂，如塞来昔布（Celebrex™; Pharmacia，Peapack，NJ）或罗非昔布（Vioxx™; Merck，怀特豪斯站，NJ），有效地调节炎症和疼痛（6）。此外，塞来昔布最近被证明可以减少高危患者的结直肠腺瘤负担（7）。然而，癌症研究人员已经报道了剂量依赖性的COX非依赖性效应，这表明除了考克斯抑制之外的机制可能是这些药物观察到的疗效的原因。在细胞水平，考克斯抑制剂已显示出抑制增殖、诱导凋亡、抑制血管生成、减少致癌物活化和刺激免疫系统（3，8）。虽然前列腺素浓度的降低可能是这些观察到的活性的基础，但也可能涉及非COX靶点和机制。例如，非选择性考克斯抑制剂已显示调节cGMP（鸟苷3，5-环一磷酸）、NF-B（核因子-B）活化、Bcl表达和过氧化物酶体蛋白结合的水平。
Cyclooxygenase (COX) inhibitors are being developed as potential agents for the prevention and treatment of cancer after a century of widespread use for inflammation, fever, and pain. Beginning in the late 1970s, researchers noted elevated concentrations of prostaglandins in neoplastic lesions, which suggested a role for arachidonic acid metabolites in tumorigenesis. Multiple lines of evidence—in vitro, in vivo, observational, and clinical—now confirm that COX inhibitors reduce prostaglandin production and the risk of colorectal, skin, and other neoplasias (1). Owing to gastrointestinal safety concerns with traditional nonselective COX inhibitors, derivatives that selectively target COX-2 have been developed for applications in arthritis, analgesia, and the treatment of neoplasia. COX-2 selective inhibitors serve as a paradigm of molecularly targeted, cytostatic, antineoplastic agents (2). COX-2 is consistently overexpressed in a large percentage and variety of human and rodent tumors (3). Pathogenic relevance to in vivo carcinogenesis was demonstrated via genetic manipulations that either eliminated (4) or induced (5) COX-2 expression, resulting in substantial tumor reduction or stimulation, respectively. Food and Drug Administration (FDA)-approved selective COX-2 inhibitors, such as celecoxib (Celebrex™; Pharmacia, Peapack, NJ) or rofecoxib (Vioxx™; Merck, Whitehouse Station, NJ), effectively modulate inflammation and pain (6). Moreover, celecoxib has recently been shown to reduce the colorectal adenoma burden in high-risk patients (7). Cancer researchers, however, have reported COX-independent effects that are dose dependent, suggesting that mechanisms other than COX suppression alone may account for the observed efficacy of these agents. At the cellular level, COX inhibitors have been shown to inhibit proliferation, induce apoptosis, inhibit angiogenesis, reduce carcinogen activation, and stimulate the immune system (3,8). Although reductions in prostanoid concentrations may underlie these observed activities, non-COX targets and mechanisms may be involved as well. For example, nonselective COX inhibitors have been shown to modulate levels of cGMP (guanosine 3,5-cyclic monophosphate), NF-B (nuclear factor-B) activation, Bcl expression, and the binding of peroxisome pro
塞来昔布可在体内防止肿瘤生长，而不对正常肠道产生毒性：体外和体内模型之间缺乏相关性。
DOI：
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发表时间：
2000
期刊：
Cancer research.
影响因子：
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作者：
Williams,CS;Watson,AJ;Sheng,H;Helou,R;Shao,J;DuBois,RN
通讯作者：
DuBois,RN
影响因子：
11.2
作者：
R. Jacoby;C. Cole;K. Tutsch;M. A. Newton;G. Kelloff;E. Hawk;R. Lubet
通讯作者：
R. Jacoby;C. Cole;K. Tutsch;M. A. Newton;G. Kelloff;E. Hawk;R. Lubet
影响因子：
158.5
作者：
Steinbach, G;Lynch, PM;Kelloff, G
通讯作者：
Kelloff, G