相關文章蒐集如下. (讀英文有困難的朋友, 請試閱用程式翻譯過的版本 )
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一種抗癌藥物能治療小鼠糖尿病
作者：佚名 文章來源：EurekAlert 更新時間：2008-11-19 15:45:08
一種用於治療白血病的藥物也能逆轉糖尿病模型小鼠的糖尿病。Cédric Louvet及其同事的一項新研究表明，伊馬替尼（格列衛®）和另一種酪氨酸激酶抑制劑藥物，可以通過抑制小鼠的免疫系統從而防止或逆轉小鼠的I型糖尿 病。伊馬替尼是被用來抑制慢性骨髓性白血病中出現的一種特定的酪氨酸激酶，但是這種藥物也會抑制其他酪氨酸激酶，其中好幾種存在於免疫系統中。
I型糖 尿病是一種自體免疫疾病，是由炎症摧毀了胰腺細胞造成的。爲了測試伊馬替尼是否能改善這種炎症從而阻止糖尿病的發生，這組科學家在糖尿病小鼠模型身上測試 了該藥。在這個過程中，他們發現用伊馬替尼或一種類似的抑制劑藥物對小鼠的自體免疫（I型）糖尿病發作前進行7周的治療，可以在治療停止之後很久防止該病 的發展。當發病之後對小鼠進行8-10周的治療後，該藥還讓80%的患病小鼠的症狀緩和。這組作者說，這種有效性表明這種對癌症治療有重要作用的藥物也可 以用於治療I型糖尿病，或許還能治療其他自體免疫疾病。相關論文發表在美國《國家科學院院刊》（PNAS）上。
推薦原始出處：
PNAS，doi: 10.1073/pnas.0810246105，Cédric Louvet，Jeffrey A. Bluestone
Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice
Cédric Louveta, Gregory L. Szota, Jiena Langa, Michael R. Leea, Nicolas Martiniera, Gideon Bollagb, Shirley Zhua, Arthur Weissc,1, and Jeffrey A. Bluestonea,1
aDiabetes Center and the Department of Medicine, University of California, San Francisco, CA 94143;
bPlexxikon, Berkeley, CA 94710; and
cDepartment of Medicine and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94143
Abstract
The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results were observed with sunitinib (Sutent), an additional approved multikinase inhibitor, suggesting that the primary target of imatinib, c-Abl, was not essential in blocking disease in this model. Additional studies with another TK inhibitor, PLX647 (targeting c-Kit and c-Fms) or an anti-c-Kit mAb showed only marginal efficacy whereas a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFRβIg, rapidly reversed diabetes. These findings strongly suggest that inhibition of PDGFR is critical to reverse diabetes and highlight a crucial role of inflammation in the development of T1D. These conclusions were supported by the finding that the adaptive immune system was not significantly affected by imatinib treatment. Finally, and most significantly, imatinib treatment led to durable remission after discontinuation of therapy at 10 weeks in a majority of mice. Thus, long-term efficacy and tolerance is likely to depend on inhibiting a combination of tyrosine kinases supporting the use of selective kinase inhibitors as a new, potentially very attractive approach for the treatment of T1D.
http://www.lascn.net:8000/news/progress/200811/751.html---------------------------------------------------------------------------------------
Type 1 Diabetes Prevented, Reversed By Two Cancer Drugs, UCSF Study Shows
Main Category: Diabetes
Also Included In: Cancer / Oncology; Biology / Biochemistry
Article Date: 18 Nov 2008 - 8:00 PST
Two common cancer drugs have been shown to both prevent and reverse type 1 diabetes in a mouse model of the disease, according to research conducted at the University of California, San Francisco. The drugs - imatinib (marketed as Gleevec) and sunitinib (marketed as Sutent) - were found to put type 1 diabetes into remission in 80 percent of the test mice and work permanently in 80 percent of those that go into remission.
The findings may offer a new weapon against this autoimmune disease, formerly called juvenile-onset diabetes, for which few drugs have been developed to address the underlying causes, the lead scientists say.
"There are very few drugs to treat type 1 diabetes, especially after disease onset, so this benefit, with a drug already proven to be safe and effective in cancer patients, is very promising," said Jeffrey Bluestone, PhD, director of the Diabetes Center at UCSF and an expert in the study of autoimmunity. "The fact that the treated mice maintained normal blood glucose levels for some time after the drug treatment was stopped suggests that imatinib and sunitinib may be 'reprogramming' their immune systems in a permanent way."
Bluestone is the A.W. and Mary Margaret Clausen Distinguished Professor of the Diabetes Center at UCSF and a senior author on the paper.
Both drugs treat cancer by inhibiting a small subset of the more than 500 tyrosine kinases, which are enzymes that modify cells' signaling proteins through a simple biochemical change. Kinases are ubiquitous agents of cell growth and proliferation, and are also involved in many diseases such as inflammation and cancer. In the immune system, tyrosine kinases are thought to be key to nearly every aspect of immunity, from the signaling that initiates a response by the immune system's T and B cells to later stages of inflammation that can cause tissue damage.
Because type 1 diabetes is caused by an autoimmune response that destroys insulin-secreting cells in the pancreas, the scientists sought to determine if one or more of the tyrosine kinases blocked by the two cancer drugs might also be responsible for the destructive inflammation in the pancreas. If so, the drugs might be promising candidates to treat diabetes.
Using a well-established mouse model for diabetes, known as the non-obese diabetic (NOD) mouse, they found that treating mice with imatinib or sunitinib before the onset of autoimmune diabetes prevented the development of the disease. Findings showed that the drugs' benefits lasted well after the seven-week treatment. Studies with mice that already had diabetes showed that imatinib put the disease into permanent remission in 80 percent of the mice after only eight to 10 weeks of treatment.
The scientists aimed to determine which of the tyrosine kinases targeted by the two cancer drugs might be responsible for triggering diabetes. To their surprise, a few of the drugs' primary targets did not appear crucial to the diabetes treatment's success.
Instead, they found that the drugs' rapid benefit appears to derive from the ability to block receptors of a tyrosine kinase not known to be implicated in diabetes, an enzyme known as platelet-derived growth factor receptor, or PDGFR. This kinase regulates cell growth and division, and also plays a key role in inflammation in a variety of settings.
"This study opens up a new area of research in the field of type 1 diabetes, and importantly, opens up exciting opportunities for developing new therapies to treat this disease and other autoimmune diseases," said Arthur Weiss, MD, PhD, UCSF professor of rheumatology and a senior author on the paper.
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Article adapted by Medical News Today from original press release.
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Weiss is the Ephraim P. Engleman Distinguished Professor and chief of rheumatology at UCSF.
The scientists will continue to study the effects of PDGFR in type 1 diabetes and have now applied for funding to perform a safety and efficacy clinical trial in patients.
Lead author of the paper is Cedric Louvet, PhD, postdoctoral fellow in the UCSF Diabetes Center. Coauthors are Shirley Zhu, PhD, UCSF Diabetes Center; Gregory Szot, PhD; Jiena Lang, BS; Michael Lee, MS, and Nicholas Martinier, BS, UCSF Diabetes Center Islet Transplant Facility; and Gideon Bollag, PhD, Plexxikon, Inc., Berkeley, Calif.
The research was funded by the National Institutes of Health and the Juvenile Diabetes Research Foundation.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, please visit http://www.ucsf.edu/.
Source: Kristen Bole
University of California - San Francisco
http://www.medicalnewstoday.com/articles/129861.php------------------------------------------------------------------------------
Cancer drug for diabetes
Published Date: 21 November 2008
A leukaemia drug "could be used to prevent and even reverse type 1 diabetes", according The Daily Telegraph this week. The newspaper highlights results from a lab study on mice with diabetes, claiming that 80% given the drug imatinib went into remission.
The mice in this study have been specifically bred to develop diabetes, and while there are similarities between this mouse model and human diabetes, there may also be differences in the development of the condition.
Therefore it is unclear as yet whether this drug, or similar drugs, would have a similar effect in humans, as only human trials could answer this question. Also, as chemotherapy drugs such as imatinib have side effects, such as inflammation of the pancreas and liver, these would have to be weighed up against any potential benefits identified in human trials.
At present there are no treatments that can reverse the effects of diabetes in humans so any new treatments that could would be an attractive option.
Where did the story come from? Dr Cedric Louvet and colleagues from the University of California conducted this research, which was funded by National Institutes of Health and the Juvenile Diabetes Research Foundation. The study was published in the peer-reviewed scientific medical journal, Proceedings of the National Academy of Sciences of the USA.
What kind of scientific study was this?This was an animal study looking at the effect of drugs in mice specially bred to develop diabetes. Diabetes is an autoimmune disease, where the body attacks and kills the cells in the pancreas, so researchers thought a drug shown to improve other autoimmune diseases in mice might also improve diabetes.
The study was specifically interested in a class of drugs called small-molecule tyrosine kinase inhibitors. Two drugs of this type were tested in this study: imatinib, which is marketed as Glivec, and sunitinib, marketed as Sutent.
Imatinib is used to treat chronic myeloid leukaemia and a rare type of stomach cancer in humans. Sutent is used in humans to treat kidney cancer and the same type of stomach cancer as imatinib.
The researchers first wanted to investigate the effect of imatinib on the risk of developing diabetes. They used mice called non-obese diabetic (NOD) mice, whose immune system spontaneously starts to attack their pancreas by two to four weeks of age. NOD mice develop full blown diabetes by about 12 to 14 weeks of age.
They divided the NOD mice into two groups, and fed one group a dose of imatinib once a day for seven weeks, starting at 12 weeks of age, when the mice were essentially pre-diabetic. The other group received no imatinib.
The researchers then measured the blood glucose levels of both sets of NOD mice to look at the proportion of mice in each group that went on to develop diabetes. They also repeated these experiments in normal mice (non-NOD mice) treated with a drug called cyclophosphamide, which causes them to develop diabetes.
The researchers then wanted to look at the effect of imatinib on established diabetes. They took NOD mice that had recently developed diabetes and treated half of them with imatinib and left the other half untreated. The researchers then measured the mice’s blood glucose levels to determine whether any of them were experiencing a remission. The researchers also repeated this experiment with sunitinib.
They also looked at what effect these drugs might be having on the immune system and various biochemical pathways.
What were the results of the study? The researchers found that by 19 weeks of age none of the NOD mice treated with imatinib had developed diabetes, while about 40% of the untreated NOD mice had developed the condition.
After imatinib treatment was stopped, 20% of treated NOD mice had gone on to develop diabetes by 30 weeks, compared with 71% of the untreated NOD mice. Most of the treated NOD mice still had not developed diabetes by 50 weeks. They found similar results in normal mice treated with cyclophosphamide, a drug that induces diabetes in mice.
In the second part of the experiment, on NOD mice which had recently developed diabetes, imatinib caused a remission in about 40% of mice after one week of treatment. None of the untreated mice experienced a remission. If imatinib treatment was stopped after 3 weeks, all of the mice developed diabetes by 15 weeks.
However, if imatinib treatment was given for 10 weeks, most of the mice remained non-diabetic up to 35 weeks, although there was a gradual increase in the proportion with diabetes over this period. The researchers reported similar findings the drug sunitinib.
What interpretations did the researchers draw from these results? The researchers concluded that using selective kinase inhibitor drugs offered a “new, potentially very attractive approach for the treatment of [type I diabetes]”, as well as other autoimmune diseases.
What does the NHS Knowledge Service make of this study?This study has added to previous animal studies that have suggested a potential role for imatinib and similar drugs in the treatment of autoimmune conditions.
Although there are similarities between human diabetes and this mouse model, there may also be differences in the processes underlying the development of the condition. Therefore it is unclear as yet whether this drug would have a similar effect in humans, and trials would have to be carried out to answer this question.
Chemotherapy drugs such as imatinib also have side effects, such as inflammation of the pancreas and liver, so these would have to be weighed up against any potential benefits identified in human trials.
As yet there are no treatments for humans that can reverse the effects of diabetes, and so any new treatments that did this would be attractive options.
The full article contains 962 words and appears in NHS Choices newspaper.
* Last Updated: 20 November 2008 3:18 AM
* Source: NHS Choices
* Location: National News
http://www.thesouthernreporter.co.uk/nhshealth/Cancer-drug-for-diabetes.4718177.jp
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Leukaemia drug tackles diabetes, too
Posted on behalf of Meredith Wadman
Imatinib (trade name Gleevec), the drug that rose to fame as a potent and lasting treatment for chronic myeloid leukemia and some other cancers has recently shown a tantalizing aptitude for targeting autoimmune diseases as well.
Both in mice with auto-immune hepatitis and arthritis and in case reports from patients with rheumatoid arthritis, psoriasis and Crohn’s disease, the thinking is that the drug, a tyrosine kinase inhibitor, is working by dampening the immune response.
Now Cedric Louvet, a postdoc in Jeffrey Bluestone’s lab at the University of California, San Francisco and colleagues have asked what Gleevec will do in what is possibly the most infamous autoimmune disease of them all: juvenile diabetes, also known as type I diabetes, in which the body’s immune system attacks and eventually destroys the insulin-producing β cells of the pancreas. The answer they found is exciting, if highly preliminary.
Louvet and his team report this week in Proceedings of the National Academy of Sciences that Gleevec cured 80% of mice afflicted with new cases of type I diabetes. Treating the mice for ten weeks led to long-lasting remission. (The diabetes reappeared in the mice when they were only treated for three weeks.) What’s more, seven weeks of treatment with the drug prevented the onset of diabetes in 80% of mice that weren’t yet diabetic but were engineered to get the disease. The protective effect was still working in a majority of them nearly one year later. Another tyrosine kinase-inhibiting drug, sunitinib (trade name Sutent), had similar effects.
The authors suggest that the drug may be throwing a wrench in the inflammatory works by targeting a tyrosine kinase that’s intimately involved in the immune response.
Posted by Alex Witze on November 18, 2008
http://blogs.nature.com/news/thegreatbeyond/2008/11/leukaemia_drug_tackles_diabete.html
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