Posted by rob on February 23, 2005 under Uncategorized | 
Clonal evolution with inv(11)(p15q22) and NUP98/DDX10 fusion gene in imatinib-resistant chronic myelogenous leukemia.
Yamamoto M, Kakihana K, Kurosu T, Murakami N, Miura O
Cancer Genet Cytogenet. 2005 Mar ; 157(2): 104-8
The BCR/ABL tyrosine kinase inhibitor imatinib has shown remarkable efficacy in treating patients with chronic myelogenous leukemia (CML). In a small portion of patients treated with imatinib, however, the disease may progress to advanced stages, frequently accompanied by cytogenetic clonal evolution with the appearance of additional chromosomal aberrations besides the Philadelphia chromosome. Here we report the appearance of an inv(11)(p15q22) as a clonal evolution in a CML patient undergoing treatment with imatinib. Leukemic cells from the patient were found to express the fusion transcript of NUP98 and DDX10, which is in accordance with previously reported cases of de novo or therapy-related acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(p15q22). Although the patient showed resistance to imatinib with the disease rapidly progressing to blast crisis, sequence analysis failed to reveal any mutation in the kinase domain of BCR/ABL that would explain the imatinib resistance. Furthermore, ex vivo treatment of leukemic cells with imatinib significantly reduced tyrosine phosphorylation of CrkL, a target of the BCR/ABL kinase. These observations raise a possibility that the NUP98/DDX10 fusion might be involved in imatinib resistance as well as in acute transformation of CML.
Clonal evolution with inv(11)(p15q22) and NUP98/DDX10 fusion gene in imatinib-resistant chronic myelogenous leukemia.
Posted by rob on February 22, 2005 under Uncategorized |
Reported February 22, 2005 Vaccine may Improve Leukemia Treatment (Ivanhoe Newswire) — A vaccine that stimulates immune response could boost the effectiveness of conventional treatment for patients with chronic myeloid leukemia, according to a new study. CML occurs when certain chromosomes, after breaking and exchanging, result in a shortened chromosome called the Philadelphia chromosome. This chromosome causes cells to make a protein that promotes abnormal division and growth. Researchers in Italy studied 16 patients with stable but detectable forms of CML. Ten of the patients were on the drug imatinib (Gleevec), and the remaining six were on the drug interferon alpha. The patients received one dose (six injections) of a vaccine targeting the faulty protein in addition to the medication they were already taking. They were evaluated after three and six doses. Results show nine of the patients on imatinib had further reduction of their disease, with five having complete cytogenetic remission (meaning no Philadelphia chromosomes were detected during cell division). Also, three out of those five had undetectable disease at a molecular level, which is extremely rare. Among the group receiving the vaccine along with interferon alpha, five out of six had their disease reduced, with two having complete cytogenetic remission. Study author Monica Bocchia, M.D., of the University of Siena in Italy remarks, “Our preliminary data suggest that the addition of this vaccine to patients treated with conventional treatment might favor further reduction of the residual disease and increase the number of patients who reach a molecular response, the best surrogate of cure for those with chronic myeloid leukemia.”
http://www.ivanhoe.com/channels/p_channelstory.cfm?storyid=10634
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A porcelaine doll by Seymour Mann is displayed at the 2005 American International Toy Fair at the Jacob Javits Convention Center in New York City.
Posted by rob on February 21, 2005 under Uncategorized |
Fumie Suguri of Japan performs during an exhibition program at the ISU Four Continents Figure Skating Championships 2005 in Gangneung, some 250 kms east of Seoul.
Posted by rob on February 20, 2005 under Uncategorized |
‘The Gates’ art project line pathways in Central Park, New York.
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Imatinib mesylate and its potential implications for gynecologic cancers.
Dushkin H, Schilder RJ
Curr Treat Options Oncol. 2005 Mar ; 6(2): 115-20
Among gynecologic malignancies, ovarian carcinoma is the most frequent cause of death, with the majority of patients presenting at advanced stage. There is a high rate of recurrence despite first-line chemotherapy. Sarcoma of the uterus, while accounting for a small percent of uterine cancers, is also associated with a high-recurrence rate and poor overall survival. Therefore, the development of novel treatment strategies is paramount. Imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a tyrosine kinase inhibitor with activity against abl, c-kit, and platelet derived growth factor receptor (PDGFR), and is approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor. Preclinical data provides evidence for c-kit and PDGFR expression in ovarian epithelial carcinomas and uterine sarcomas and have led to clinical trials evaluating the use of imatinib in these malignancies. Additionally, inhibition of PDGFR signaling has been proposed as an effective mechanism of chemotherapy by lowering tumor interstitial fluid pressure. Recent data have also suggested benefit with metronomic scheduling of cytotoxic agents at lower doses at more frequent dosing intervals, in combination with other targeted therapies. While activity of this agent remains to be established, further studies of imatinib in gynecologic malignancies are warranted, to demonstrate not only single-agent activity and the enhancement of cytotoxicity of other antineoplastic agents.
Imatinib mesylate and its potential implications for gynecologic cancers.
Posted by rob on under Uncategorized |
Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.
Ren R
Nat Rev Cancer. 2005 Feb 18;
Imatinib, a potent inhibitor of the oncogenic tyrosine kinase BCR-ABL, has shown remarkable clinical activity in patients with chronic myelogenous leukaemia (CML). However, this drug does not completely eradicate BCR-ABL-expressing cells from the body, and resistance to imatinib emerges. Although BCR-ABL remains an attractive therapeutic target, it is important to identify other components involved in CML pathogenesis to overcome this resistance. What have clinical trials of imatinib and studies using mouse models for BCR-ABL leukaemogenesis taught us about the functions of BCR-ABL beyond its kinase activity, and how these functions contribute to CML pathogenesis?
Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.
Posted by rob on under Uncategorized |
Imatinib mesylate and its potential implications for gynecologic cancers.
Dushkin H, Schilder RJ
Curr Treat Options Oncol. 2005 Mar ; 6(2): 115-20
Among gynecologic malignancies, ovarian carcinoma is the most frequent cause of death, with the majority of patients presenting at advanced stage. There is a high rate of recurrence despite first-line chemotherapy. Sarcoma of the uterus, while accounting for a small percent of uterine cancers, is also associated with a high-recurrence rate and poor overall survival. Therefore, the development of novel treatment strategies is paramount. Imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a tyrosine kinase inhibitor with activity against abl, c-kit, and platelet derived growth factor receptor (PDGFR), and is approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor. Preclinical data provides evidence for c-kit and PDGFR expression in ovarian epithelial carcinomas and uterine sarcomas and have led to clinical trials evaluating the use of imatinib in these malignancies. Additionally, inhibition of PDGFR signaling has been proposed as an effective mechanism of chemotherapy by lowering tumor interstitial fluid pressure. Recent data have also suggested benefit with metronomic scheduling of cytotoxic agents at lower doses at more frequent dosing intervals, in combination with other targeted therapies. While activity of this agent remains to be established, further studies of imatinib in gynecologic malignancies are warranted, to demonstrate not only single-agent activity and the enhancement of cytotoxicity of other antineoplastic agents.
Imatinib mesylate and its potential implications for gynecologic cancers.
Posted by rob on under Uncategorized |
Imatinib mesylate and its potential implications for gynecologic cancers.
Dushkin H, Schilder RJ
Curr Treat Options Oncol. 2005 Mar ; 6(2): 115-20
Among gynecologic malignancies, ovarian carcinoma is the most frequent cause of death, with the majority of patients presenting at advanced stage. There is a high rate of recurrence despite first-line chemotherapy. Sarcoma of the uterus, while accounting for a small percent of uterine cancers, is also associated with a high-recurrence rate and poor overall survival. Therefore, the development of novel treatment strategies is paramount. Imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a tyrosine kinase inhibitor with activity against abl, c-kit, and platelet derived growth factor receptor (PDGFR), and is approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor. Preclinical data provides evidence for c-kit and PDGFR expression in ovarian epithelial carcinomas and uterine sarcomas and have led to clinical trials evaluating the use of imatinib in these malignancies. Additionally, inhibition of PDGFR signaling has been proposed as an effective mechanism of chemotherapy by lowering tumor interstitial fluid pressure. Recent data have also suggested benefit with metronomic scheduling of cytotoxic agents at lower doses at more frequent dosing intervals, in combination with other targeted therapies. While activity of this agent remains to be established, further studies of imatinib in gynecologic malignancies are warranted, to demonstrate not only single-agent activity and the enhancement of cytotoxicity of other antineoplastic agents.
Imatinib mesylate and its potential implications for gynecologic cancers.
Posted by rob on under Uncategorized |
Imatinib mesylate and its potential implications for gynecologic cancers.
Dushkin H, Schilder RJ
Curr Treat Options Oncol. 2005 Mar ; 6(2): 115-20
Among gynecologic malignancies, ovarian carcinoma is the most frequent cause of death, with the majority of patients presenting at advanced stage. There is a high rate of recurrence despite first-line chemotherapy. Sarcoma of the uterus, while accounting for a small percent of uterine cancers, is also associated with a high-recurrence rate and poor overall survival. Therefore, the development of novel treatment strategies is paramount. Imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a tyrosine kinase inhibitor with activity against abl, c-kit, and platelet derived growth factor receptor (PDGFR), and is approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor. Preclinical data provides evidence for c-kit and PDGFR expression in ovarian epithelial carcinomas and uterine sarcomas and have led to clinical trials evaluating the use of imatinib in these malignancies. Additionally, inhibition of PDGFR signaling has been proposed as an effective mechanism of chemotherapy by lowering tumor interstitial fluid pressure. Recent data have also suggested benefit with metronomic scheduling of cytotoxic agents at lower doses at more frequent dosing intervals, in combination with other targeted therapies. While activity of this agent remains to be established, further studies of imatinib in gynecologic malignancies are warranted, to demonstrate not only single-agent activity and the enhancement of cytotoxicity of other antineoplastic agents.
Imatinib mesylate and its potential implications for gynecologic cancers.
Posted by rob on February 19, 2005 under Uncategorized |
A dancer of Berlin’s opera house Staatsoper Unter den Linden, rehearses in a giant aquarium a ballet scene of Henry Purcell’s opera ‘Dido and Aeneas’ staged by Sasha Waltz.
Posted by rob on February 18, 2005 under Uncategorized |
Public release date: 18-Feb-2005
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Contact: Bill Schaller
617-632-4090
Dana-Farber Cancer Institute
Study finds new designer drug is potent treatment for chronic myelogenous leukemia
More potent and highly selective therapy effective in treating Gleevec-resistant disease
BOSTON–A laboratory study led by researchers at Dana-Farber Cancer Institute has shown that a potent and highly selective therapy for chronic myelogenous leukemia (CML) may ultimately be more effective than Gleevec®, the current standard of care. The researchers report in the February issue of Cancer Cell that the new compound, AMN107, is about 20 times more potent than Gleevec and is effective in treating Gleevec-resistant disease in model systems. Discovered by and in development with Novartis Pharma AG, AMN107 is a small molecule tyrosine kinase inhibitor.
“While Gleevec represents a major treatment advance for CML – approximately 95 percent of patients treated with Gleevec achieve remission – there clearly is a need for therapies that produce longer remissions, are active against advanced disease, and can be used when Gleevec loses effectiveness,” says Dana-Farber’s James Griffin, MD, senior author of the study.
Gleevec shuts down CML by blocking the function of Bcr-Abl, the abnormal tyrosine kinase protein in the leukemic cells that causes them to grow too quickly. However, it does not bind very tightly to this protein, and patients can develop a resistant type of Bcr-Abl that no longer binds to Gleevec at all.
Using rational drug design to circumvent these shortcomings, researchers at Novartis determined the crystal structure of Bcr-Abl, and then constructed compounds that would lock into the receptor more securely than Gleevec. Investigators at Dana-Farber tested the new compounds to measure their effectiveness against CML in laboratory cell cultures and mice with the disease.
Data from the study published in Cancer Cell showed that in experiments with laboratory samples of CML cells, AMN107 killed the cells more effectively than Gleevec. In follow-up studies with mice with a human form of CML, AMN107 produced lengthier remissions than Gleevec and triggered remissions in animals in which the disease had become resistant to Gleevec. Side effects in the animals were minimal.
Synthesized in August 2002, AMN107 entered early Phase I clinical studies in May 2004 – 21 months later. Data presented last December at the American Society of Hematology showed that AMN107 had demonstrated significant clinical activity in the most challenging setting: Gleevec resistant accelerated and blast crisis CML patients.
“We’re very encouraged by the results so far,” remarks Griffin, who is also a professor of medicine at Harvard Medical School. “This is an elegant example of how rational drug design –– developing drugs based on a molecular understanding of cell structures and processes –– can be used to attack human diseases.”
The findings contribute to a larger Dana-Farber research effort, dubbed the “Kinase Project,” which seeks to identify abnormal tyrosine kinases — enzymes that spark or halt growth — in cancer cells and test agents known to act against them.
The Cancer Cell study’s lead author is Ellen Weisberg, PhD, of Dana-Farber. Co-authors include researchers at Dana-Farber, Novartis, Brigham and Women’s Hospital, and Children’s Hospital Boston.
###
The preclinical study was conducted as part of a research collaboration between Novartis Pharma AG and Dana-Farber.
REVISED RELEASE: Clarification that Novartis Pharma AG is discoverer of AMN107
Dana-Farber Cancer Institute (www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
Study finds new designer drug is potent treatment for chronic myelogenous leukemia
Posted by rob on under Uncategorized |
[Realgar nano-particles induce apoptosis and necrosis in leukemia cell lines K562 and HL-60]
Ning N, Peng ZF, Yuan L, Gou BD, Zhang TL, Wang K
Zhongguo Zhong Yao Za Zhi. 2005 Jan ; 30(2): 136-40
OBJECTIVE: To examine the growth-inhibitory, apoptosis- and necrosis-inducing effects of realgar nano-particles (RNP) in human chronic myelogenous leukemia cell line K562 and acute myeloid leukemia cell line HL-60, and to find out the chemical species with efficacy. METHOD: A “solvent-relay” strategy was used for the preparation of RNP suspension. Cell viability was determined by MTT assay. Cell apoptosis and necrosis were characterized with Annexin V-PI double staining in association with flow cytometry and with morphological examination with Hoechst 33258 staining. Parallel experiments with arsenous acid (H3AsO3), the dominant form of arsenic trioxide in the solution, were conducted for comparison. RESULT: The mean diameter of RNP was 159.0 nm. RNP showed growth-inhibitory effect on both cell lines. The double staining test indicated that RNP induced both apoptosis and necrosis, and this was further confirmed by morphological examination. CONCLUSION: RNP induced both apoptosis and necrosis in leukemia cell lines K562 and HL-60. Thioarsenite species with both As-O and As-S bonds may be the active intermediates in the RNP.
[Realgar nano-particles induce apoptosis and necrosis in leukemia cell lines K562 and HL-60]
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Label-free detection of small-molecule-protein interactions by using nanowire nanosensors.
Wang WU, Chen C, Lin KH, Fang Y, Lieber CM
Proc Natl Acad Sci U S A. 2005 Feb 16;
Development of miniaturized devices that enable rapid and direct analysis of the specific binding of small molecules to proteins could be of substantial importance to the discovery of and screening for new drug molecules. Here, we report highly sensitive and label-free direct electrical detection of small-molecule inhibitors of ATP binding to Abl by using silicon nanowire field-effect transistor devices. Abl, which is a protein tyrosine kinase whose constitutive activity is responsible for chronic myelogenous leukemia, was covalently linked to the surfaces of silicon nanowires within microfluidic channels to create active electrical devices. Concentration-dependent binding of ATP and concentration-dependent inhibition of ATP binding by the competitive small-molecule antagonist STI-571 (Gleevec) were assessed by monitoring the nanowire conductance. In addition, concentration-dependent inhibition of ATP binding was examined for four additional small molecules, including reported and previously unreported inhibitors. These studies demonstrate that the silicon nanowire devices can readily and rapidly distinguish the affinities of distinct small-molecule inhibitors and, thus, could serve as a technology platform for drug discovery.
Label-free detection of small-molecule-protein interactions by using nanowire nanosensors.
Posted by rob on under Uncategorized |
Leukemia Vaccine Looks Promising
Vaccine Boosts Body’s Attack on Cancer Cells
By Jeanie Lerche Davis
WebMD Medical News Reviewed By Brunilda Nazario, MD
on Thursday, February 17, 2005
Feb. 17, 2005 – An experimental vaccine could provide a new treatment for people with chronic myeloid leukemia (CML), a new study shows.
Not only does the vaccine boost the body’s immune system to fight leukemia, but it also helps get rid of the underlying cause of the leukemia. Currently, this can only be done with a bone marrow transplant.
This could help lead to a cure for CML, which affects about 4,500 Americans each year.
In chronic myeloid leukemia, overproduction of an abnormal protein leads to very high numbers of cancerous white blood cells.
Current treatment, such as Gleevec, targets this abnormal protein. Although Gleevec normally gets rid of any detectable cancer cells, the cancer-causing protein still remains.
And that’s what researcher Monica Bocchia, MD, a hematologist with Siena University in Siena, Italy, wanted to address. Her study appears in this week’s issue of The Lancet.
The researchers tested the use of a cancer vaccine to help trigger the body’s immune system to recognize and attack cells with the CML protein.
Cancer vaccines are not vaccines in the way that most people think of vaccines. Unlike most vaccines, which help prevent diseases, cancer vaccines are added to treatment in someone who already has cancer.
In her study, she and her colleagues recruited 16 patients with chronic myeloid leukemia. All had received treatment with either 12 months of Gleevec or 24 months of interferon alpha, another CML treatment. The patients’ disease was stable.
Each was given six injections two weeks apart. The vaccine actually contained the abnormal protein itself. This stimulates the immune system to launch an attack against cancerous cells containing the abnormal protein.
Nine Gleevec-treated patients showed progressive reduction of their remaining disease. Five patients went into complete remission; three had no evidence that the CML protein was still lurking. All but one of the six interferon-alpha-treated patients had a good response; two went into complete remission.
The researchers say the vaccine was effective at stimulating an immune system attack against the cancer cells with the abnormal protein.
They say adding the vaccine to current CML treatment may help get rid of remaining cancer cells.
In addition, the vaccine was able to get rid of the cancer-causing protein — a sign that the CML has been cured.
The vaccine is experimental and not yet available to the public.
Leukemia Vaccine Looks Promising
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LONDON (Reuters) – An experimental vaccine that boosts the immune system has produced good results in treating patients with chronic myeloid leukaemia (CML), Italian scientists said on Friday.
Treatment of the condition — a slow-progressing cancer in which too many white blood cells are made in the bone marrow — was revolutionised in 2001 with the approval of Novartis AG’s drug Glivec. But that medicine does not eradicate the disease completely, and patients can develop resistance.
Monica Bocchia of the University of Siena and her colleagues found that a vaccine targeting a protein derived from a faulty chromosome, which is implicated in CML, improved the condition of patients significantly.
A group of 16 patients with stable disease, who were taking either Glivec or interferons, were given six vaccinations of the experimental vaccine. All but one showed an improvement, and seven reached complete cytogenetic remission, with no faulty chromosomes detected during cell division.
“Our preliminary data suggest that the addition of this vaccine to patients treated with conventional treatment might favour further reduction of the residual disease,” Bocchia reported in the Lancet medical journal.
Bocchia said her group was seeking funding for larger randomised clinical trials of the vaccine, which was developed by her scientific team rather than a commercial company.
Glivec, which is sold as Gleevec in the United States, is Novartis’s second-biggest product, with sales in 2004 of $1.6 billion.
Both Novartis and Bristol-Myers Squibb Co are working on experimental drugs aimed at patients with CML who no longer respond to treatment with Glivec.
Reuters | Latest Financial News / Full News Coverage
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Pale Male and Lola, seen here, a pair of red-tailed hawks evicted from their perch on a swank New York apartment building, are back and, according to their many supporters, are starting a new family
Posted by rob on under Uncategorized |
Pale Male and Lola, seen here, a pair of red-tailed hawks evicted from their perch on a swank New York apartment building, are back and, according to their many supporters, are starting a new family
Posted by rob on February 17, 2005 under Uncategorized |
Fireworks explode over the ski jump stadium during the opening ceremony of the Nordic World Championships in Oberstdorf, southern Germany.
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Researchers from Novartis Pharmaceuticals, Basel, Switzerland, and Dana-Farber Cancer Institute, Boston, released a new report on AMN107, a targeted therapy for chronic myelogenous leukemia (CML) that, they say, may be more effective than Gleevec (imatinib).
The report [Ellen Weisberg, et al., Cancer Cell, vol.7, pp.129-141 (2005)] details the characterization of the molecule in vitro and in experimental Bcr-Abl-driven mouse models of leukemia. Dana-Farber reports the drug to be about 20 times more potent than Gleevec and effective in treating these resistant model systems. “Relapse is often associated with point mutations in Bcr-Abl that reduce the binding affinity of imatinib,” the study states. In Novartis’ previous work they determined the crystal structure of Bcr-Abl, and used the complex to construct AMN107 with more potent and selective binding properties. The study now describes two new structures of Abl in complex with AMN107.
In mice AMN107 produced lengthier remissions than Gleevec, they say, and triggered remissions in animals in which the disease had become resistant to Gleevec. Side effects in the animals were reported as minimal.
The findings contribute to a larger Dana-Farber research effort, dubbed the “Kinase Project,” which seeks to identify abnormal tyrosine kinases, enzymes that spark or halt growth in cancer cells and test agents known to act against them.
AMN107 is in phase I clinical trials at M.D. Anderson Cancer Center.
By Elizabeth Tolchin
Bioscience Technology
