圖片來自Christine E. Eyler et al. Glioma Stem Cell Proliferation and Tumor Growth Are Promoted by Nitric Oxide Synthase-2, Cell, Volume 146, Issue 1, 53-66, 8 July 2011, DOI：10.1016/j.cell.2011.06.006.
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2012年3月31日-4月4日在芝加哥市舉行的美國癌癥研究協(xié)會(American Association for Cancer Research, AACR)年度會議上，來自美國威斯康星大學麥迪遜分校醫(yī)學與公共衛(wèi)生學院放射學副教授Jamey Weichert博士和他的同事們描述了一種藥物CLR1404能夠顯影和破壞很多種惡性腫瘤和一種癌干細胞類型,。
威斯康星大學醫(yī)院門診綜合腦瘤項目主任和醫(yī)學與公共衛(wèi)生學院癌干細胞科學家John Kuo博士,，正在研究利用藥物CLR1404靶向多形性膠質(zhì)母細胞瘤(glioblastoma multiforme, GBM)干細胞是否能夠治療這種致命性的腦瘤。
在第一項實驗中,，Kuo和Weichert描述了CLR1404如何降低GBM干細胞活性,，抑制GBM生長并改善GBM模式動物存活。
第二項實驗表明用于正電子發(fā)射斷層掃描成像(PET imaging)的藥物CLR1404含有一種放射性同位素碘-124,，能夠顯著性地和選擇性成像小鼠中的惡性腫瘤,，并且詳細地描述了這種藥物如何實現(xiàn)這種功能。
第三項實驗解釋用另一種放射性元素碘-131標記的藥物CLR1404作為一種放射治療試劑,，能夠讓腫瘤萎縮，并且讓人類癌癥模式動物壽命延長10年以上,。
只需一次注射,，含有碘-124的CLR1404就進入血液中,，選擇性地進入惡性腫瘤而不是正常組織內(nèi)部。10天之后，這種藥物除了在惡性腫瘤細胞存在外,，就不在體內(nèi)存在,。CLR1404在原發(fā)性惡性腫瘤和轉(zhuǎn)移瘤中堆積，但在良性腫瘤中不積累,。
Weichert說,，“我們發(fā)現(xiàn)癌細胞通過脂筏(lipid raft)來攝取CLR1404，而且相比于正常細胞,，癌細胞含有更加豐富的脂筏,。”
碘-131標記的藥物CLR1404也能夠選擇性地靶向癌細胞。在進行一次注射后,，癌細胞接受來自細胞內(nèi)的持續(xù)性致死放射線輻射,，而正常組織相對而言則不受到傷害。
Weichert'領(lǐng)導的研究小組在多種惡性腫瘤如肺癌,、腎癌,、結(jié)腸癌、卵巢癌,、子宮癌,、胰腺癌、前列腺癌和三陰性乳腺癌中測試藥物CLR1404的療效,。單次靜脈注射能夠顯著性地抑制腫瘤生長,，并延長這些癌癥模式動物的壽命。
Kuo和Weichert也發(fā)現(xiàn)CLR1404也能夠靶向和破壞癌干細胞,。
Kuo說,，“像大多數(shù)癌干細胞一樣，GBM干細胞通常抵抗治療,，而且我們認為它們能夠?qū)е麓竽X中腫瘤復發(fā),。靶向GBM干細胞可能在改善病人治療結(jié)果上發(fā)揮著關(guān)鍵性作用。”
Kuo將來自GBM患者的膠質(zhì)瘤干細胞(glioma stem cell)移植到小鼠中,，從而導致腫瘤在小鼠大腦中生長,。當他注射基于CLR1404試劑的另一種診斷性物質(zhì)CLR1501時，它進入膠質(zhì)瘤干細胞中,，并照射它們,。即便是這種腫瘤從小鼠中移除并把膠質(zhì)瘤干細胞再次分離時，這些膠質(zhì)瘤干細胞依然發(fā)光,，這就表明這種試劑能夠延長滯留在它們內(nèi)部。
Weichert說,，“藥物CLR1404在惡性腫瘤和癌干細胞中獨特的延長滯留是這種藥物發(fā)揮出診斷性和治療性作用所必需的,。”
Kuo領(lǐng)導的研究小組利用CLR1404處理體外培養(yǎng)的膠質(zhì)瘤干細胞，發(fā)現(xiàn)它能夠極大地降低這些干細胞的增殖和存活能力。當這些接受藥物處理的膠質(zhì)瘤干細胞移植到動物時,，腫瘤生長受到抑制并且動物存活能力加強,。
Kuo說，“癌細胞能夠滲透進附近正常的腦部組織,，這就限制了我們當前所采用的手術(shù)摘除,、化療和放療治療GBM的療效性。CLR1404相關(guān)聯(lián)的藥物試劑在癌細胞中的特異性滯留提示著人們能夠利用它們在細胞水平上潛在性地作為一種抗癌療法,，同時對正常腦細胞的傷害最小化,。”
2003年，Weichert在Cellectar公司對藥物CLR1404進行商品化銷售,。2011年Cellectar公司被Novelos Therapeutics公司收購,。如今，Novelos Therapeutics公司正在基于CLR1404平臺開發(fā)5種化合物,。(生物谷：towersimper編譯)
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One Compound Detects and Treats Malignant Tumors and Certain Cancer Stem Cells
Madison, Wisconsin - More than a decade of laboratory research at the University of Wisconsin has proven that a single chemical compound may both detect and treat malignant tumors and certain cancer stem cells.
In three posters presented at the annual meeting of the American Association for Cancer Research (AACR) in Chicago, March 31-April 4, UW-Madison researchers describe exciting advances involving CLR1404, described as a "diapeutic" agent that can both image and destroy a wide range of malignant tumors and the one type of cancer stem cells examined so far.
The presentations are based on basic research in the lab of Dr. Jamey Weichert, associate professor of radiology at the UW School of Medicine and Public Health (SMPH) and a member of the UW Carbone Cancer Center (CCC).
Clinicians at the UW School of Medicine and Public Health and elsewhere are interested in assessing CLR1404's potential. Several clinical trials evaluating both the cancer imaging and therapeutic capabilities of CLR1404 are under way at the Carbone Cancer Center, with more scheduled to begin soon.
Dr. John Kuo, director of the Comprehensive Brain Tumor Program at UW Hospital and Clinics and a cancer stem-cell scientist at the School of Medicine and Public Health, is studying the possibility of using CLR1404 to treat glioblastoma multiforme (GBM), a deadly form of brain cancer, by targeting GBM stem cells.
In one of the American Association for Cancer Research posters (#3495), Kuo and Weichert describe how CLR1404 decreases glioblastoma stem cell activity, suppresses GBM growth and improves animal survival.
Another poster (#5740) shows that the PET imaging version of CLR1404, which contains iodine-124, dramatically and selectively illuminates malignant tumors in mice. The poster details how the compound does this.
The third poster (#3831) explains how CLR1404 labeled instead with iodine-131 works as a radiotherapy agent to shrink tumors and extend life in more than 10 animal models of human cancer.
With one injection, iodine-124-containing CLR1404 enters the bloodstream and selectively penetrates and is retained by malignant tumors rather than normal tissues. After 10 days, the compound clears the body but remains in malignant tumor cells. CLR1404 accumulates in both primary malignant tumors and metastases, but not in benign tumors.
"We have found that CLR1404 is taken up by cancer cells through lipid rafts, which are much more abundant in cancer cells compared to normal cells," says Weichert.
Replacing iodine-124 with iodine-131 generates the radiotherapeutic version of CLR1404, which also selectively targets cancer cells. After a single injection, cancer cells are exposed to sustained lethal radiation from inside the cell, while normal tissues are relatively unharmed.
Weichert's team has tested the treatment in many different malignancies, including cancers of the lung, kidney, colon, ovary, uterus, pancreas, prostate, brain and breast, including the most difficult to treat, triple negative breast cancer. A single intravenous injection significantly suppressed tumor growth and extended the life of animals with these cancers.
In a collaborative effort between their two laboratories, Kuo and Weichert found that CLR1404 also targets and cripples cancer stem cells.
"Like most stem cells, GBM stem cells typically resist therapy, and we think they may cause tumors to recur in the brain," says Kuo, assistant professor of neurological surgery and human oncology at the School of Medicine and Public Health, and chair of the brain tumor group at the Carbone Cancer Center. "Targeting of GBM stem cells is probably critical for improving patient outcome."
Kuo implanted glioma stem cells from patients with GBM into mice - and tumors grew in their brains. When he injected another diagnostic form of the agent, CLR1501, it entered the stem cells and illuminated them. Even after the tumors were removed from the mice and the stem cells were isolated again, the pluripotent cells still glowed, indicating extended retention of the agent.
"This unique prolonged retention of the compound in malignant tumors and cancer stem cells is central to the diagnostic and therapeutic actions of CLR1404," says Weichert.
Kuo's team then treated the stem cells in culture with CLR1404 and found greatly reduced cell proliferation and survival. When the treated stem cells were implanted in animals, tumor growth was suppressed and animal survival increased.
"Infiltration of cancer cells into adjacent normal brain limits the efficacy of the surgery, radiation and chemotherapy we currently use to treat GBM," Kuo says. "Specific retention of CLR1404-related agents in cancer cells suggests its potential use as an anti-cancer therapy on the cellular level - especially for the invading cells that escape current therapies - while minimizing damage to normal brain cells."
Weichert commercialized CLR1404 in 2003 in a company called Cellectar, based in Madison, which merged with Novelos Therapeutics a year ago. Novelos, now based in Madison, is developing five compounds based on the CLR1404 platform.
Date Published: 04/03/2012
