谢谢分享 很好的资料
学习谢谢分享
谢谢分享
向橙子学习！
谢谢分享，辛苦，每天看你在群里一点点的分享，日积月累，已经达到专家水平了。向你学习。
很不错啊，橙子！
美丽无名 发表于 2014-12-16 10:51
很不错啊，橙子！
学习了，谢谢分享！
MEK 抑制剂可诱发特定类型皮疹
MEK 抑制剂不同寻求的药物高敏症病例报道在 JAMA Dermatology 网络版上已有描述，这些报道涉及独特中央微黑性皮疹。3 名接受不同 MEK 抑制剂（ 司美替尼、Cobimetinib 及曲美替尼）治疗的患者出现 2 级或 3 级的皮疹，均与独特微黑皮疹有关联，华盛顿大学 Patel 博士及同事报道称。
作为一项临床试验的一部分，一位前列腺癌男性患者接受司美替尼治疗，他在初始治疗 12 天之后发生 2 级的一般性皮疹及瘙痒。他出现中央微黑的弥漫性靶样斑块。司美替尼与其它研究药物治疗被中止，随后该患者被配给局部类固醇治疗药物，4 周之后皮疹完全消失。由于碱性磷酸酶水平升高及出现疲劳，这位患者未继续使用这款研究药物。
一位正使用 Cobimetinib 及其它药物治疗转移性黑色素瘤的 40 多岁妇女在治疗到 28 天时，出现周围微黑的聚结性荨麻疹斑块。病理组织学检查显示浅层血管周围淋巴组织浸润有罕见嗜酸性粒细胞。治疗中止 7 天后，该患者开始口服强的松，Cobimetinib 重新以较低剂量给药。Cobimetinib 重新治疗 1 年后，未再次发生皮疹，Patel 博士与同事报道称。
第 3 位患者是一位 50 多岁的转移性黑色素瘤妇女，她以曲美替尼结合其它药物治疗 7 周后出现程度为 3 级的皮疹。日益恶化的荨麻疹斑块围绕着弥漫性微黑。在曲美替尼治疗停止一周后，开始口服强的松治疗，曲美替尼治疗也重新开始，皮疹未再次发生。
“如我们的患者所显示的那样，这种 MEK 抑制剂相关皮疹的治疗可包括药物假期及口服糖皮质激素药物治疗，然后重新使用该药物较低剂量治疗，此时皮疹不会再次出现，”Patel 博士与其同事写道。
MEK 抑制剂以促分裂原活化蛋白激酶激酶通路为靶点。曲美替尼已被批准用于治疗晚期黑色素瘤，而有十多个其它 MEK 抑制剂正在临床试验中（包括司美替尼和 Cobimetinib）被测试用于黑色素瘤及其它实体器官恶性肿瘤治疗，包括前列腺癌、肝细胞癌、结直肠癌及非小细胞肺癌，文章作者指出称。
Vitamin C halts growth of aggressive forms of colorectal cancer in preclinical study
Model of a vitamin C molecule. Black is carbon, red is oxygen, and white is hydrogen. Credit: Public Domain High levels of vitamin C kill certain kinds of colorectal cancers in cell cultures and mice, according to a new study from Weill Cornell Medicine investigators. The findings suggest that scientists could one day harness vitamin C to develop targeted treatments.
Colorectal cancer is the third most-common cancer diagnosed in the United States, with about 93,090 new cases each year. Around half of those cases harbor mutations in the KRAS and BRAF genes; these forms of the disease are more aggressive and don't respond well to current therapies or chemotherapy.
In a study, published Nov. 5 in Science, a team of researchers from Weill Cornell Medicine, Cold Spring Harbor Laboratory, Tufts Medical Center, Harvard Medical School and The Johns Hopkins Kimmel Cancer Center found that high doses of vitamin C—roughly equivalent to the levels found in 300 oranges—impaired the growth of KRAS mutant and BRAF mutant colorectal tumors in cultured cells and mice. The findings could lead to the development of new treatments and provide critical insights into who would most benefit from them.
"Our findings provide a mechanistic rationale for exploring the therapeutic use of vitamin C to treat colorectal cancers that carry KRAS or BRAF mutations," said senior author Dr. Lewis Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center and the Margaret and Herman Sokol Professor in Oncology Research at Weill Cornell Medicine.
The conventional wisdom is that vitamin C improves health in part because it can act as an antioxidant, preventing or delaying some types of cell damage. However, Dr. Cantley and his colleagues discovered that the opposite was true in regards to high-dose vitamin C's therapeutic effects for the KRAS and BRAF forms of colorectal cancer—they occur as a result of inducing oxidation in these cancer cells.
In an oxygen-rich environment such as human arteries, a fraction of vitamin C, also called ascorbic acid, becomes oxidized and is transformed into a new compound called dehydroascorbic acid (DHA). Scientists have known for some time that a specific membrane protein, known as glucose transporter GLUT1, enables both glucose and DHA to enter cells—an activity not afforded to ascorbic acid. But it was less clear what DHA does once inside the cells.
In the study, investigators show that DHA acts like a Trojan horse. Once inside, natural antioxidants inside the cancer cell attempt to convert the DHA back to ascorbic acid; in the process, these antioxidants are depleted and the cell dies from oxidative stress.
"While many normal cells also express GLUT1, KRAS-mutant and BRAF-mutant cancer cells typically have much higher levels since they require a high rate of glucose uptake in order to survive and grow," Dr. Cantley said. "Also, KRAS and BRAF mutant cells produce more reactive oxygen species than normal cells and therefore need more antioxidants in order to survive. This combination of characteristics makes these cancer cells far more vulnerable to DHA than normal cells or other types of cancer cells."
Although Dr. Cantley cautioned that these results need to be evaluated in the setting of a human clinical trial, the pre-clinical findings may offer a promising new treatment strategy for the KRAS or BRAF forms of the disease, perhaps as part of a combination therapy. The investigators say their study could lead to the development of new biomarkers that could help physicians determine who would most benefit from treatment. These insights may also have implications for other hard-to-treat cancers that express high levels of GLUT1 transporter, such as renal cell carcinoma, bladder cancer and pancreatic cancer.
Vitamin C has multiple effects on cellular functions in addition to its anti- or pro-oxidant functions, so it will be important to study the effects of high-dose vitamin C on normal and immune cells, said lead author Dr. Jihye Yun, a postdoctoral fellow in Dr. Cantley's lab.
"Further study is definitely needed to expand our understanding of these processes. But now that we know the mechanisms, we can utilize the knowledge wisely to get the desired effects," she said.
"This is not a therapy that you would want to wander into blindly without knowledge of what is going on in your tumor," Dr. Cantley added.
Dosing recommendations also need to be determined. Therapeutic benefit would likely require intravenous injections, as oral doses are not absorbed efficiently in the intestine to achieve the high serum concentration of vitamin C needed to cause toxicity to these cancer cells. Recent phase I clinical trials conducted on humans to test toxicity have shown that intravenous infusion of vitamin C at doses that converted to similar levels of serum as the Cantley mice trials had good safety profiles.
"Our hope is that our study will inspire the scientific community to take a fresh look at this safe and inexpensive natural molecule and stimulate both basic and clinical research regarding vitamin C as a cancer therapy," Dr. Yun said.
More information: Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH, Science 6 November 2015: 619. DOI: 10.1126/science.aaa5004
Provided by: Weill Cornell Medical College
http://m.medicalxpress.com/news/2015-11-vitamin-halts-growth-aggressive-colorectal.html#categ
Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH
ABSTRACT
More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations, and are often refractory to approved targeted therapies. We report that cultured CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, ROS accumulates and inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibiting GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impaired tumor growth in Apc/KrasG12D mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.
http://www.sciencemag.org/content/early/2015/11/04/science.aaa5004