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Protein That Fuels Ovarian Cancer Identified and Shut Down By Researchers
ScienceDaily (Feb. 28, 2008) — A protein that stimulates blood vessel growth worsens ovarian cancer, but its production can be stifled by a tiny bit of RNA wrapped in a fatty nanoparticle, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in the Journal of the National Cancer Institute.
\"The protein interleukin-8 (IL-8) is a potential therapeutic target in ovarian cancer,\" said senior author Anil ***, M.D., professor in the M. D. Anderson Departments of Gynecologic Oncology and Cancer Biology.
The paper demonstrates that high IL-8 expression in tumors is associated with advanced tumor stage and earlier death for ovarian cancer patients. Lab experiments and research in a mouse model show that short interfering RNA (siRNA) can cut IL-8 expression, reducing tumor size by attacking its blood supply.
\"This comprehensive analysis - with human data, animal data and lab experiments to highlight the molecular mechanisms involved - helps us develop the new targets needed for a more effective approach against ovarian cancer,\" *** said.
Interleukin-8 is overexpressed in many types of cancer and has previously been shown to promote tumor growth, new blood vessel growth known as angiogenesis, and metastasis, the spread of cancer to other organs. \"In the long run, this research will have applications in other cancers as well,\" *** said.
His research focuses on ovarian cancer, for example, while senior co-author Menashe Bar-Eli, Ph.D., professor in M. D. Anderson's Department of Cancer Biology, examines IL-8's role in melanoma.
Impact on survival
Ovarian cancer is often detected in late stages. Initial treatment includes surgery and taxane- or platinum-based chemotherapy regimens that keep the cancer at bay for a time in most patients. Recurrence is common and often lethal.
To examine IL-8's role in ovarian cancer, the researchers analyzed tumors from 102 patients diagnosed and treated between 1988 and 2006 at M. D. Anderson and the University of Iowa. Of those, 43 had tumors with high levels of IL-8 and 59 had low levels. The median survival of those with high IL-8 tumors was 1.62 years, compared with 3.79 years for those with low expression of the protein.
All 43 tumors with high expression of IL-8 were of high grade and 42 of 43 were advanced, either stage III or IV tumors. By comparison, 10 of 59 tumors with low IL-8 expression were early stage tumors and six were of low grade.
Shrinking tumors
Genes transcribe single strands of RNA that in turn are \"read\" by ribosomes to produce proteins. siRNAs are short, double-stranded bits of RNA capable of halting that process. The team confirmed in a lab experiment that a specific siRNA silences IL-8 and then tested it against two lines of ovarian cancer in a mouse model.
***, Gabriel Lopez-Berestein, M.D., professor in M. D. Anderson's Department of Experimental Therapeutics, and colleagues are building an arsenal of siRNAs capable of silencing genes that produce cancer-promoting proteins. They packaged siRNA that stymies IL-8 into a small ball of fat known as a liposome, a combination they developed to overcome a problem - siRNA is hard to deliver to tumors.
Tumors shrank by a median of 32 percent and 52 percent in the two cancer lines among mice that received injections of the IL-8 siRNA liposome compared to those receiving control siRNA or empty liposomes.
Mice that got both the IL-8 siRNA plus the taxane-based chemotherapy drug docetaxel had median tumor weight reduction of 90 percent and 98 percent in the two cell lines. Mice with control siRNA plus docetaxel saw reductions of 67 and 84 percent.
Finally, they tested the approach in mice with an ovarian cancer cell line known to be resistant to taxane-based drugs such as docetaxel. IL-8 siRNA alone reduced the size of these tumors by 47 percent, and when combined with docetaxel reduced tumor size by 77 percent, suggesting that the combination re-sensitizes a resistant tumor to taxanes.
The team gauged the impact of IL-8 siRNA on tumor blood supply by measuring the density of blood vessels in the tumor. The IL-8 siRNA alone reduced blood vessel density by 34 percent and 39 percent in two cancer lines.
Clinical Prospects
\"These are encouraging results. We want to move one of our siRNA agents into the clinic to test its potential for therapy,\" *** said, \"and then in the longer term, we'll consider moving additional siRNA agents into the clinical arena.\"
The IL-8 siRNA liposome is the third developed by ***'s and Lopez-Berestein's team. Two others target the oncoproteins FAK and EphA2. The EphA2 siRNA liposome is closest to Phase I clinical trial, with required toxicology studies nearly complete. A clinical trial could begin within a year.
Methods used to inject siRNA in high volumes for research purposes are impractical for human therapy. *** and Lopez-Berestein developed the liposomal approach to ensure that the siRNA reaches the cell intact so it can silence the targeted gene. Their research has shown that the liposome penetrates deeply into cells to deliver its siRNA.
Research reported in JNCI was funded by grants from the National Cancer Institute of the National Institutes of Health, including M. D. Anderson's Specialized Program of Research Excellence in Ovarian Cancer; the Ovarian Cancer Research Fund, Inc.; and the Zarrow Foundation.
Co-authors with ***, Bar-Eli and Lopez-Berestein are first author William Merritt, Yvonne G. Lin, Whitney Spannuth, Aparna Kamat, Liz Han, Charles Landen, and Nicholas Jennings, all of M. D. Anderson's Department of Gynecologic Oncology; Robert Langley and Gabriel Villares, both of M. D. Anderson's Department of Cancer Biology; Angelina Sanguino, of M. D. Anderson's Department of Experimental Therapeutics; Mavis Fletcher of the Nebraska Medical Center Department of Pathology and Microbiology; Koen De Geest of the University of Iowa Hospitals and Clinics Department of Obstetrics and Gynecology; and Susan Lutgendorf of the University of Iowa Department of Psychology.
http://www.sciencedaily.com/releases/2008/02/080226162848.htm
科学日报（2008年2月28日）——德克萨斯大学安德森癌症中心在国立癌症研究院的杂志上报道了一种刺激血管生长的蛋白可使卵巢癌恶化，但是包裹在脂肪状纳米颗粒中的微小RNA可以阻止这样的结果发生。妇产肿瘤学和癌症生物学系的Anil ***, M.D.教授说：“白介素8(IL-8)就是一种潜在的治疗卵巢癌的靶子。”这篇论文表明肿瘤中高表达的IL-8与卵巢癌患者晚期肿瘤和早期死亡相关联。小鼠模型研究表明小干扰RNA(siRNA)可以阻止IL-8的表达，通过减少肿瘤血供使肿瘤缩小。***说：“综合人、动物数据和实验室研究我们强调了所涉及的分子机制，从而帮助我们为更有效的治疗卵巢癌开辟了新的目标。”IL-8在许多肿瘤中过高表达，它可以促进肿瘤生长，新生血管生长和转移使得肿瘤向其他器官蔓延。***说：“这项研究最终还可应用于其他肿瘤。”
例如他的研究集中在卵巢癌上，而癌症生物学系的Menashe Bar-Eli教授则致力于IL-8在黑色素瘤中作用的研究。
对生存的影响
卵巢癌通常发现时已是晚期了。大多数患者的初始治疗包括手术和以紫杉烷或铂为基础的化疗。复发很常见也是致命的。为了研究IL-8在卵巢癌中的所起的作用，研究者分析了1998年到2006年期间在安德森和爱荷华大学被诊断和治疗的102名卵巢癌患者发现，43名患者体内IL-8处于高水平，59名患者体内IL-8低水平表达。高IL-8水平癌症患者的中位存活率为1.62年，而低IL-8水平的癌症患者中位生存率为3.79年。43位高表达IL-8的肿瘤患者均是高度分化，其中42位已是晚期，或者是III期或者是IV期肿瘤。相反，59名低表达IL-8的肿瘤患者中有10名处于早期肿瘤，6名是低分化的。
肿瘤缩小
核糖体依次“阅读”单链RNA表达蛋白。siRNA是小双链RNA，所以可阻止蛋白的表达。研究小组在实验中证实特异的siRNA可阻止IL-8表达，然后再检测其在小鼠模型中对抗卵巢癌的两个癌系。安德森中心实验治疗学系的Gabriel Lopez-Berestein教授和同事建了一个siRNA库，可使表达促癌蛋白的基因沉默。他们把阻止IL-8表达的siRNA装进脂质体中，这样便可阻止肿瘤转移。两种癌系的小鼠在注射IL-8 siRNA脂质体后相比较对照组或者接受空脂质体注射的小鼠其肿瘤缩小的中位百分比分别为32%和52%。接受IL-8 siRNA加上紫衫烷为基础的化疗药紫杉萜治疗的两种细胞系的小鼠其肿瘤中位重量分别减少90%和98%。而对照组siRNA加紫杉萜治疗的小鼠分别减少了67%和84%。最后，他们检测了对紫衫烷为基础的药物如紫杉萜抵抗的卵巢癌细胞系的小鼠。只有IL-8 siRNA可使肿瘤减小47%，而联合紫杉萜治疗可使肿瘤减小77%，从而表明联合治疗可使对紫衫烷抵抗的肿瘤恢复敏感。研究组通过检测肿瘤血管密度估测了IL-8 siRNA对肿瘤血供的影响。只有IL-8 siRNA可使两种癌系的血管密度减少34%和39%。
临床前景
***说：“这些结果是令人鼓舞的。我们希望将siRNA试剂应用于临床来检测其治疗的潜力，今后我们将考虑将其他siRNA试剂运用于临床。”IL-8 siRNA脂质体是***和Lopez-Berestein小组研究的第三个靶目标。另两个靶目标是癌蛋白FAK 和EphA2。EphA2 siRNA脂质体与I期临床实验最密切，其所需的毒物学研究基本已完成。临床实验可能在一年内开始。大量注射siRNA用于科研的方法不适用于人类的治疗。*** 和Lopez-Berestein发明了脂质体方法来确保siRNA可以直接到达细胞以便其能使靶基因沉默。他们的研究表明脂质体深入细胞可传递其siRNA.
本研究是由国立卫生研究院国立癌症研究所资助的，包括卵巢癌研究的安德森特别项目，卵巢癌研究基金公司，Zarrow基金。 |
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发表于 2008-3-21 11:54:36