[英文新闻]Celecoxib May Fight Liver Cancer

StephenW

http://www.medscape.com/viewarticle/743308
Celecoxib May Fight Liver Cancer

Fran Lowry

May 24, 2011 — The cyclooxygenase 2 (COX-2) inhibitor celecoxib, which has shown anticancer effects in malignancies of the colon, lung, and prostate, may also be a candidate for the treatment of liver cancer, according to new research published online April 13 in Cancer Prevention Research.
Scientists, led by Yan Liu, PhD, from Ohio State University in Columbus, report that celecoxib may have anticancer activity because it blocks the interleukin 6/signal transducer and activator of transcription 3 (STAT3) pathway and causes apoptosis in liver  cancer cells.
They made their discovery in human hepatocellular carcinoma (HCC) cells.
Jiayuh Lin, PhD, an associate professor of paediatrics at Ohio State and senior author of the study, told Medscape Medical News he would advocate taking a COX-2 inhibitor as a preventive measure.

Dr. Jiayuh Lin

"Based on the ability of celecoxib to inhibit both STAT3 and COX-2, it may have some beneficial effects in cancer prevention," he said.
Dr. Lin explained that there is growing evidence demonstrating an association between chronic liver inflammation and HCC development. STAT3, which is associated with inflammation and cellular transformation, is activated in human HCC tissue but not in normal  human liver tissues.
The researchers found that celecoxib decreased STAT3 phosphorylation to cause the liver cancer cells to self-destruct. They also found that celecoxib blocked exogenous interleukin-6–induced STAT3 phosphorylation and nuclear translocation.
Importantly, they also observed that when celecoxib was combined with doxorubicin or sorafenib, more HCC cells in culture were killed.
"Each chemotherapy drug alone will reduce the growth of cancer cells, but when each drug was combined with celecoxib, a greater growth suppression effect was observed," Dr. Lin said. "Therefore, we believe that celecoxib can be combined with other anticancer  drugs to reduce drug resistance caused by interleukin-6 STAT3 signals."
This research adds to the growing evidence for a possible role for COX-2 inhibition in various cancers.
                        Cardiovascular Concerns                    
However, cardiovascular concerns have long been an issue with this class of drugs.
In a study that was presented at the 2008 Annual Meeting of the American Association for Cancer Research, Monica Bertagnolli, MD, from Brigham and Women's Hospital in Boston, Massachusetts, reported that celecoxib reduced the 5-year rate of advanced colorectal  adenomas by 41% in high-risk patients who took the drug for 3 years.
However, subjects had to discontinue taking the drug as concerns about cardiovascular safety began to emerge.
Nevertheless, the protection from adenomas continued after use of the drug was stopped, and Dr. Bertagnolli concluded that COX-2 inhibitors are promising in patients who are at risk of developing adenomas and who do not have cardiovascular risk factors.
In another study that was presented the same year at the Annual Meeting of the American Society of Clinical Oncology, Edward Kim, MD, from the M.D. Anderson Cancer Center in Houston, Texas, reported that celecoxib was able to reduce the expression of Ki-67,  a biomarker associated with bronchial premalignant lesions, and could have a chemoprotective effect against lung cancer.
The study, which was conducted in current or former smokers with at least a 20 pack-year smoking history, was also halted because of fears of cardiovascular toxic effects but resumed after advisers to the US Food and Drug Administration recommended that  it be continued.
                        Medscape Medical News invited Craig A. Elmets, MD, professor and chair, Department of Dermatology, University of Alabama at Birmingham, to comment on the use of COX-2 inhibitors for chemoprevention.
"I think we can add hepatocellular carcinoma to the potential types of cancer which will respond to NSAIDs [nonsteroidal anti-inflammatory drugs]," he said.
Dr. Elmets recently headed a multicenter randomized controlled trial that found that celecoxib may be effective for prevention of squamous cell carcinomas and basal cell carcinomas in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma  skin cancers.
"We treated patients with nonmelanoma skin cancers for 9 months, and in the patients who received celecoxib there was a greater than 50% reduction in the number of new nonmelanoma skin cancers that developed compared to a control group that didn't receive  celecoxib," he said in an interview.
Dr. Elemets said that when his study was started, concerns about the cardiovascular adverse effects with celecoxib had not yet surfaced. Similar to the other trials, his was stopped when these concerns came to light. However, during the 9 months that patients  took celecoxib no increase in cardiovascular risk was seen, he noted.
                        Possible Alternatives to Celecoxib                    
Dr. Elmets admitted that if the COX-2 inhibitors are going to be taken to prevent cancer, then the cardiovascular risk they pose could become an issue.
"People need to be on these drugs on a chronic basis for preventive benefit," he explained. "Celecoxib blocks the cyclooxygenase 2 enzyme, but there are a number of other drugs that also block COX-2 that have much less of a cardiovascular risk, so these  may be ideal for prevention of various types of cancers."
Sulindac (Clinoril, Merck) is one, he said. "Combined with difluoromethylornithine, it produces a dramatic reduction in the number of colorectal adenomas, so I think that there is definitely something going on here with regard to chemoprevention."
A COX-2 inhibitor may be particularly useful in hepatitis B–positive patients who are at risk for HCC.
"Hepatocellular carcinoma is not a common malignancy in the US, but in patients who are hepatitis B positive, this may be a drug that should be considered because mortality rate for hepatocellular carcinoma is really quite high," he said.
"Naproxen has much less of a cardiovascular effect than the other NSAIDs, so there would be quite a bit of interest in looking at naproxen," he added.
Using lower NSAID doses or screening people for cardiovascular risk factors may be other strategies that will enable these drugs to be used as effective chemopreventive agents. "So might using these drugs intermittently or using them in combination with  other drugs at much lower doses than are normally used," Dr. Elmets said.
                        Dr. Li, Dr. Lin, and Dr. Elmets have disclosed no relevant financial relationships.                     
                        Cancer Prev Res. Published online April 13, 2011 Text                    

StephenW

2011年5月24日 - 环氧化酶2（COX - 2的）抑制剂塞来昔布，它表现出了结肠癌，肺癌，前列腺肿瘤的抗癌效果，还可能为治疗肝癌的人选，根据新的研究网上公布4月13日在癌症预防研究。

科学家，由Yan Liu博士，美国俄亥俄州立大学哥伦布，报告导致塞来昔布可能有抗癌活性，因为它会阻止白细胞介素6/signal转导和转录激活因子3（STAT3）的途径和肝癌细胞凋亡的原因。

他们提出了在人肝细胞癌（HCC）的细胞的发现。

Jiayuh林，博士，副教授的儿科在俄亥俄州立大学和研究的资深作者，告诉WebMD医学新闻，他会主张以作为一项预防措施，一种COX - 2抑制剂。
林医生Jiayuh

“关于塞来昔布能够抑制STAT3和基于双方的COX - 2，它可能有预防癌症的一些有益的影响，”他说。

林医生解释说，有越来越多的证据表明慢性肝脏炎症之间和肝癌发展协会。 STAT3的，这是与炎症和细胞转化相关，是人类的肝癌组织中激活，但在正常肝组织。

研究人员发现，STAT3磷酸化昔下降导致肝癌细胞自我毁灭。他们还发现，外源昔阻止白细胞介素6诱导STAT3的磷酸化和核转。

重要的是，他们还观察到，当昔是索拉非尼与阿霉素或相结合，培养更多的肝癌细胞被杀死。

“每个化疗药物单独将减少癌细胞的生长，但是当每个药物塞来昔布，结合了更大的增长抑制效果观察，”林博士说。 “因此，我们认为，塞来昔布可与其他抗癌药合用，以减少耐药性白细胞介素-6 STAT3的信号引起的。”

本研究增加了一个对COX - 2在各种癌症中的作用日益明显的抑制作用。

心血管关注

然而，心血管问题长期以来一直与这类药物的一个问题。

在一项发表在2008年的癌症研究，莫尼卡Bertagnolli医师，布里格姆美国协会会议和妇女在波士顿，马萨诸塞州医院的研究报告说，塞来昔布减少了41先进大肠腺瘤5年率％在高风险患者谁花了3年的药物。

然而，受试者停止服用这种药物的关于心血管安全问题开始出现。

然而，从腺瘤保护继续使用该药物后暂停，博士Bertagnolli认为COX - 2抑制剂的患者是谁正处于发展腺瘤的风险，谁不希望有心血管危险因素。

在另一个提出了在临床肿瘤学，爱德华Kim医师，美国社会的年度会议同年从MD安德森癌症中心在休斯敦，得克萨斯州，研究报告说，塞来昔布能减少Ki - 67的表达，支气管癌前病变相关的生物标志物，并可能对肺癌chemoprotective效果。

这项研究是在目前或曾经吸烟者进行至少一包20年的吸烟史，也停止了因心血管毒性作用的担忧，但恢复后，美国食品和药物管理局顾问的建议，继续此项工作。

WebMD医学新闻克雷格A Elmets邀请医师，教授兼系主任，皮肤科，阿拉巴马大学伯明翰部评论中COX - 2抑制剂的化学预防使用。

“我认为我们可以添加肝癌的潜在的癌症种类，将响应的NSAIDs [非甾体抗炎药]，”他说。

最近Elmets博士为首的多中心随机对照试验发现，塞来昔布可为鳞状细胞癌和个人有广泛的光化谁在破坏和非黑色素瘤皮肤癌的高危险群的发展基底细胞癌的预防作用。

“我们治疗9个月，非黑色素瘤皮肤癌患者，在患者谁收到昔出现了一个新的非黑色素瘤皮肤，发达国家相比，对照组未接受昔癌症，大于50％减少”他在接受采访时说。

Elemets博士说，当他的研究已经启动，有关塞来昔布的心血管不良影响的关注还没有浮出水面。类似于其他审判，他被停止时，这些问题被揭发。然而，在9个月，患者服用塞来昔布没有被视为心血管疾病的危险增加，他指出。

可能替代昔

博士Elmets承认，如果在COX - 2抑制剂将要采取的预防癌症，心血管疾病的危险，那么它们对可能会成为问题。

“人们需要对这些药物都必须在预防慢性利益的基础上，”他解释说。 “昔阻断环氧合酶-2的酶，但也有其他药物，也阻断COX - 2的有很大的心血管风险低，所以这些可能是不同类型的癌症预防理想的数字。”

舒林酸（Clinoril，默克公司）是其中之一，他说。 “与二氟相结合，产生了在大肠腺瘤数目急剧减少，因此我认为肯定是有东西在这里发生化学预防方面。”

一个COX - 2抑制剂可能特别有用的乙肝阳性患者谁在肝癌的风险。

“肝癌是不是在美国常见的恶性肿瘤的患者，谁是B型肝炎阳性，但，这可能是一个应该考虑，因为肝癌死亡率相当高的速度实在是药物，”他说。

“萘普生具有很大的比其他NSAIDs的心血管作用较少，因此会有相当多的兴趣在寻找在萘普生位，”他补充说。

使用NSAID的心血管危险因素降低剂量或筛选的人可能有其他的战略，将使这些药物被视为有效的化学预防剂。 “因此，使用这些药物可能会间歇性或使用与其他药物合用大大低于通常使用的剂量他们，”博士Elmets说。

李医生，林医生，博士和Elmets宣告没有相关财务关系。

癌症上一页水库。线上发表于2011年4月13日文本