Kidney Cancer Drug Attacks A Major Type Of Acute Myeloid Leukemia

Daily Science Journal (Feb. 1, 2008) — A drug used to treat kidney cancer also targets a genetic mutation active in about one third of patients with acute myeloid leukemia (AML), the most common and lethal form of adult leukemia, researchers at The University of Texas M. D. Anderson Cancer Center report in the Jan. 29 edition of the Journal of the National Cancer Institute.

In a Phase I clinical trial, the drug sorafenib reduced the median percentage of leukemia cells circulating in the blood from 81 percent to 7.5 percent and in the bone marrow from 75.5 percent to 34 percent among AML patients whose leukemia includes the FLT3-ITD mutation. Two patients had circulating leukemia cells, or blasts, drop to zero.

"AML patients with this mutation have a particularly poor prognosis, so this highly targeted drug appears to be a significant step forward in leukemia therapy," says senior author Michael Andreeff, M.D., Ph.D., professor in M. D. Anderson's Department of Stem Cell Transplantation and Cellular Therapy and Department of Leukemia.

The JNCI paper reports the drug's effect in lab experiments, a mouse model of the disease, and in a Phase I study of 16 patients with relapsed or resistant AML known to have the FLT3-ITD mutation.

There have been no major side effects in the clinical trial to date, so no maximum tolerated dose has been reached, Andreeff notes. The drug has little effect on cells with normal versions of the gene and does not interfere with normal blood cell formation.

A Phase I/Phase II clinical trial for AML is open at M. D. Anderson that combines sorafenib with the standard of care chemotherapy combination for AML, idarubicin and cytosine arabinoside. Presently, the trial is open for relapsed patients and those newly diagnosed with high-risk disease, says study co-author Jorge Cortes, M.D., professor in M. D. Anderson's Department of Leukemia. As safety and dose escalation research progress, sorafenib will be made available to other patients and assume a role in frontline therapy.

About 14,000 new cases of AML are diagnosed annually in the United States and the disease kills about 9,000 people each year. AML is characterized by swift proliferation of immature white blood cells in the blood and bone marrow that crowds out normal cells, leaving patients exposed to infection, severe anemia, and bleeding.

While major progress has been made treating some forms of leukemia and lymphoma, acute myeloid leukemia has seen less improvement in recent years. Andreeff says that's because AML exploits multiple molecular pathways and that these pathways differ from one type of AML to the next.

Andreeff and colleagues have shown that molecular pathways subverted and used by AML collude with each other, so when one pathway is blocked, the others redouble their efforts to fuel the disease.

"Here we have a great response against an important mutation, but sorafenib alone will not cure patients," Andreeff notes. Combination therapy will be required. Andreeff and colleagues are planning to examine other sorafenib combinations against FLT3-mutant disease.

After in vitro tests showed that sorafenib inhibited the growth of FLT3 mutant leukemia cell colonies, the research team tested the medication in a mouse model of the disease. Sorafenib-treated mice had a median survival of 36.5 days compared with 20.5 days in untreated mice. Bioluminescence imaging showed widespread cancer growth in untreated mice and barely detectable disease in those that had received the drug.

Sorafenib, known commercially as Nexavar® and co-developed by Bayer AG and Onyx Pharmaceuticals, already is approved for advanced renal cell carcinoma and inoperable liver cancer by the U.S. Food and Drug Administration. It is being tested against other solid tumors.

The drug targets both tumor cell growth and angiogenesis - new blood vessels woven by cancer to sustain itself - by targeting two classes of kinases, which are enzymes that affect proteins by attaching phosphate groups to them.

Sorafenib's antileukemia effects appear to be superior to early results of new therapies under development that more narrowly target the FLT3 gene. Andreeff says the drug's ability to hit multiple kinases probably accounts for this, but the exact molecular mechanisms involved require further study.

Co-authors with Andreeff and Cortes are lead author Weiguo Zhang, M.D., Ph.D., who conducted most of the project's laboratory research, Marina Konopleva, M.D., Ph.D., Yue-xi Shi, Teresa McQueen, Xiaoyang Ling, Ph.D., all of the department of Stem Cell Transplantation and Cellular Therapy; David Harris, Zeev Estrov, M.D., and Alfonso Quintas-Cardama, M.D. all of the Department of Leukemia; and David Small, M.D. of Johns Hopkins University School of Medicine.

Research was funded by grants from the National Cancer Institute, a Leukemia SPORE Career Development Award, and the Cancer Therapy Evaluation Program.

Adapted from materials provided by University of Texas M. D. Anderson Cancer Center.

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Pathway To Turn Off Immune System Cells Discovered

Daily Science Journal (Feb. 1, 2008) — University of Minnesota researchers have discovered a new way to turn genes off in human T cells, a type of white blood cell that helps the immune system fight infections.

Turning off genes, through a process known as mRNA decay, is important for regulating the body's immune response after fighting infection. This research could lead to development of new drugs that turn off the immune system in patients with autoimmune diseases -- such as rheumatoid arthritis and lupus. It could also prevent cancer cells from dividing.

Researchers used a novel approach that combines molecular biology and computational analysis to identify mRNA sequence responsible for turning off T cells.

"Although this study analyzed T cells, this pathway is present in all human cells," said Paul Bohjanen, M.D., Ph.D., co-director of the Center for Infectious Diseases and Microbiology Translational Research (CIDMTR) and principal investigator of the study. "Knowledge from this study can be applied to help researchers better understand other types of cells and how they function."

During an infection, T cells turn on and divide to help clear the infection from the body. After the infection is cleared, the cells need to turn off so the body can return to a stable condition. If the cells do not turn off, however, they can cause damage to the body and can potentially develop into cancer cells.

This research is important because to date, understanding the mechanisms that turn off cells has not been very well understood.

Researchers measured the rate of mRNA decay for each of the approximately 6,000 genes in human T cells. That information was then analyzed by George Karypis, Ph.D., associate professor of computer science, and his colleagues at the Minnesota Supercomputing Institute, using complex computer programs to identify a sequence present in mRNA that was destroyed rapidly in the cell. Bohjanen and his colleagues performed molecular biology experiments to confirm that this sequence targets mRNA for destruction and was responsible for turning off genes in activated T cells.

"This discovery would not have been possible without the interdisciplinary collaboration between molecular biologists and computer scientists," Bohjanen said. The collaboration between Bohjanen and Karypis was facilitated by Irina Vlasova, M.D., Ph.D., research associate in Bohjanen's molecular biology laboratory, who received training in computational biology through a Minnesota Supercomputing Institute fellowship.

The research is published in the February 1 issue of Molecular Cell. The research was conducted by researchers at CIDMTR, Department of Microbiology, Department of Medicine, Department of Computer Science, and Division of Biostatistics.

The research was funded by grants from the National Institutes of Health, the Minnesota Medical Foundation, the Minnesota Supercomputing Institute, the Lymphoma Research Foundation, and the Swedish Research Council.

Adapted from materials provided by University of Minnesota, via EurekAlert!, a service of AAAS.

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New Skin-healing Chemicals, Green Tea And The 'Asian Paradox'

Daily Science Journal (Aug. 30, 2007) — Researchers have made synthetic lipids called pseudoceramides that are involved in skin cell growth and could be used in treating skin diseases in which skin cells grow abnormally.

Ceramides are lipids found in the outermost skin layer called the stratum corneum, which is made of dead skin cells and mainly serves as a physical barrier. Ceramides' main biological function is to control how skin cells grow and differentiate -- a process through which skin cells become specialized.

Scientists have created in the laboratory synthetic ceramides, called pseudoceramides, to treat skin diseases such as atopic dermatitis, a form of eczema characterized by red, flaky and very itchy skin; psoriasis, a disease that causes red scaly patches on the skin; and glucocorticoid-induced epidermal atrophy, in which the skin shrinks due to skin cell loss.

Jeung-Hoon Lee and colleagues have developed a new series of pseudoceramides and examined their effects on skin cells. They found that three pseudoceramides called K6PC-4, K6PC-5, and K6PC-9 significantly increased the amount of proteins produced when skin cells differentiate. These results were obtained both on cultured skin cells and on a reconstituted epidermis. K6PC-4, K6PC-5, and K6PC-9 may be used to treat skin diseases arising from abnormal growth of skin cells, the scientists concluded.

Article: "Novel synthetic ceramide derivatives increase intracellular calcium levels and promote epidermal keratinocyte differentiation," by Yoo Bin Kwon, Chang Deok Kim, Jong-Kyung Youm, Hyung Sub Gwak, Byeong Deog Park, Seung Hun Lee, Saewha Jeon, Bo Joong Kim, Young-Joon Seo, Jang-Kyu Park, and Jeung-Hoon Lee

Adapted from materials provided by American Society for Biochemistry and Molecular Biology, via EurekAlert!, a service of AAAS.

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Green Tea And The 'Asian Paradox'

There is a lower incidence of cardiovascular disease and cancer in Asia where people smoke heavily, which may be accounted for by high consumption of tea, particularly green tea, according to a review article published by a Yale School of Medicine researcher.

"We do not yet have a full explanation for the 'Asian paradox,' which refers to the very low incidence of both heart disease and cancer in Asia, even though consumption of cigarettes is greater than in most other countries," said Bauer Sumpio, M.D., professor and Chief of Vascular Surgery in the Department of Surgery. "But we now have some theories."

Sumpio, the lead author of the review in the Journal of the American College of Surgeons, said he and his colleagues reviewed more than 100 experimental and clinical studies about green tea in writing the article.

He said one theory is that the average 1.2 liters of green tea consumed daily by many people in Asia offers the anti-oxidant protective effects of the polyphenolic EGCG. EGCG may prevent LDL oxidation, which has been shown to play a key role in the pathophysiology of arteriosclerosis. EGCG also reduces the amount of platelet aggregation, regulates lipids, and promotes proliferation and migration of smooth muscle cells, which are all factors in reducing cardiovascular disease, he said.

Sumpio said other reports show that EGCG prevents growth of certain tumors. Tea, according to studies, also can improve gastrointestinal function, alcohol metabolism, kidney, liver and pancreatic function, protect skin and eyes and alleviate arthritis. Tea has been used in managing and preventing allergies, diabetes, bacterial and viral infections, cavities, reduce or cure diseases with an inflammatory component and improve neurologic and psychological health.

"More studies are necessary to fully elucidate and better understand green tea's method of action, particularly at the cellular level," Sumpio said. "The evidence is strong that green tea consumption is a useful dietary habit to lower the risk for, as well as treat, a number of chronic diseases. Certainly, however, smoking cessation is the best way to prevent cardiovascular disease and cancer."

Reference: Journal of the American College of Surgeons 202: 813-825 (May 2006)

Adapted from materials provided by Yale University.

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Programmed Cell Death Protects Against Infections

Daily Science Journal (Jun. 15, 2007) — They are the largest group of white blood cells: neutrophil granulocytes kill microorganisms. Neutrophils catch microbes with extracellular structures nicknamed Neutrophil Extracellular Traps (NETs) that are composed of nucleic acid and aggressive enzymes.

Neutrophil granulocytes have trapped Shigella bacteria in NETs. (Image: Dr. Volker Brinkmann, Max Planck Institute for Infection Biology)

A group of scientists lead by Arturo Zychlinsky at the Max-Planck-Institute for Infectious Biology in Berlin, Germany discovered, how the neutrophils form this snaring network (Journal of Cell Biology, online, January 8, 2007). Once triggered, the cells undergo a novel program leading to their death. While they perish, the cells release the content of their nuclei. The nucleic acid, mingled with bactericidal enzymes, forms a lethal network outside the cell. Invading bacteria and pathogenic fungi get caught and killed in the NETs.

Every minute, several million neutrophils leave the bone marrow and are ready to defend the body of invading germs. They are the immune system’s first line of defence against harmful bacteria and migrate into the tissue at the site of infection to combat pathogens. For more than hundred years it was known that neutrophil granulocytes kill bacteria very efficiently by devouring them. After eating the germs neutrophils kill tehm with antimicrobial proteins.

The group of scientists lead by Arturo Zychlinsky at the Max-Planck-Institute for Infectious Biology discovered a second killing mechanism: neutrophil granulocytes can form web-like structures outside the cells composed of nucleic acid and enzymes which catch bacteria and kill them. The scientists were able to generate impressive micrographs of these nets. But it remained a mystery how the granulocytes could mobilise the contents of their nuclei and catapult it out of the cells.Only after lengthy live cell imaging and biochemical studies it became clear how neutrophils make NETs. The cells get activated by bacteria and modify the structure of their nuclei and granules, small enzyme deposits in the cytoplasm.

"The nuclear membrane disintegrates, the granules dissolve, and thus the NET components can mingle inside the cells", explains Volker Brinkmann, head of the microscopy group. At the end of this process, the cell contracts until the cell membrane bursts open and quickly releases the highly active melange. Once outside the cell, it unfolds and forms the NETs which then can trap bacteria.

Surprisingly, this process is as effective as devouring bacteria: "NETs formed by dying granulocytes kill as many bacteria as are eaten up by living blood cells", says Arturo Zychlinsky. Thus, neutrophils fulfil their role in the defence battle even after their deaths.

Adapted from materials provided by Max Planck Society.

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