Posted by rob on November 28, 2005 under Uncategorized | 
A significant proportion of Generation Rx – perhaps too much of it – unfolds as a straightforward business story, in which we witness Big Pharma, at first tentatively and then with increasing euphoria, slough off its old fuddy-duddy ambiance and traditional restraints to embrace what the author calls a promotional “bacchanal,” today spending $12 billion a year, “between $8,000 and $15,000 annually per physician to sell its wares.” The direct payola that doctors receive from this scheme – from pens and notebooks to cash payments, trips and visits from sexy young sales reps dispensing back rubs, suggesting a “pharmaceutical lap dance” more than “an old-fashioned sales call” – puts the record industry to shame
Posted by rob on November 22, 2005 under Uncategorized |
By STEVE MITCHELL
WASHINGTON, Nov. 21 (UPI) — An analyst firm predicts Bristol Myers Squibb’s chronic myelogenous leukemia drug dasatinib, which is currently in phase 2 trials, could be as clinically and commercially successful as Novartis’ Gleevec.
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Novartis may still be in the running, however, because their AMN-107, which also is in phase 2, appears to have the potential to tackle Gleevec-resistant CML cases.
Dasatinib and AMN-107 are second-generation protein tyrosine kinase inhibitors, and both stand to gain accelerated approval by the Food and Drug Administration if they pan out in clinical trials, said Nish Saini a senior oncology analyst with Datamonitor who authored a new report on the future of CML therapies.
“Should the ongoing Phase II studies confirm dasatinib’s clinical benefit in Gleevec-resistant or -intolerant patients, Datamonitor believes it is likely to garner accelerated approval from the FDA,” Saini said. “Similarly, should Phase II data consolidate the demonstrable Phase I activity of AMN-107, Novartis has the opportunity to drive accelerated approval.”
Novartis might have a competitive advantage because of its experience marketing Gleevec. If Novartis can capitalize on this background and establish AMN-107 as a standard for Gleevec-resistant CML, the company could gain a secure foothold in the CML market, Saini said.
Gleevec, a protein tyrosine kinase inhibitor launched in 2002, proved enormously successful due to its ability to provide effective treatment with little toxicity. The drug had sales of nearly $1 billion in 2004. However, many CML cases are resistant to Gleevec and there is a need for new medications to fill that gap.
“Resistance, along with Gleevec’s relatively modest response rate amongst patients with advanced disease indicate the need for novel, efficacious second line treatment strategies to counter these challenges,” Saini said.
Decision Resources, an analyst firm in Waltham, Mass., said in a May report that it expected the anticipated launches of dasatinib and AMN-107 to “increase patient drug consumption by offering a viable, and likely durable, second-line pharmacological approach to the treatment of chronic CML.”
Decision Resources differs from Datamonitor, however, and expects BMS’ dasatinib to have the biggest influence on the market.
The drug “is active against a wider range of resistance-conferring mutations compared with AMN-107 and is widely hailed as the more promising agent,” the Decision Resources report said. The approval of the drug for first-line treatment in combination with Gleevec “would have enormous impact on the CML market,” the report stated.
Decision Resources predicted the market for CML therapies will grow by nearly 12 percent per year from 2004 to 2009 due to the launch of new medications for the disease, but then it is expected to drop to less than 1 percent per year until 2014.
Other protein tyrosine kinase inhibitors in development that could have an impact, include Aria Pharmaceuticals’ AP-23464 and Wyeth’s SKI-606, Decision Resources said. Both are in preclinical development.
Another medication that could factor into the CML market in 2006 is Supergen/MGI Pharma’s decitabine. Decision Resources said this drug is pre-registered in the United States and Europe for myelodysplastic syndrome, although it is not yet approved by any regulatory agency. Decitabine is expected to be used off-label beginning in 2006 in patients with accelerated- and blastic-phase CML. These forms of CML can be difficult to treat but they have responded well to decitabine.
If new protein tyrosine kinsase inhibitors are launched, Decision Resources said, they will likely have a negative impact on the development of other CML medications, such as ChemGenex’s Ceflatonin and Cell Therapeutics’ Trisenox.
The report stated that doctors said they would be reluctant to enroll patients in trials for these drugs if they are eligible for studies involving protein tyrosine kinase inhibitors.
Copyright 2005 by United Press International. All Rights Reserved.
BMS’ dasatinib expected to rival Gleevec
Posted by rob on November 20, 2005 under Uncategorized |
Neynaber S, Wolff H, Plewig G, Wienecke R
J Dtsch Dermatol Ges. 2004 Jul ; 2(7): 588-91
Four case reports of patients with myeloproliferative syndrome receiving therapy with hydroxycarbamide (synonymous: hydroxyurea) and developing streaky longitudinal pigmentation appeared in fingernails and toenails several months after starting this therapy. BACKGROUND: Pigmentation of finger- and toenails presents a wide range of differential diagnostic considerations. They can be of infectious, melanocytic or exogenous origin or caused by metabolic disorders. PATIENTS AND METHODS: Three women and one man, ranging in age from 62 and 87 years, were treated with hydroxycarbamide for myeloproliferative syndrome or chronic myelogenous leukemia for five to twelve years. All four patients were Fitzpatrick skin types II. RESULTS: Several months after starting this therapy, they developed streaky longitudinal pigmentation of their fingernails and toenails. In two patients, these findings were diagnosed by chance, whereas two patients sought dermatological advice because of nail pigmentation. In two of the patients the longitudinal pigmentation disappeared a few month after discontinuation of hydroxycarbamide. The melanonychia persisted in another patient, while the fourth was lost to follow-up. CONCLUSIONS: When melanonychia is identified in hematology-oncology patients, a careful medical history should be obtained. A list of medications is crucial, since hydroxycarbamide causes nail pigmentation. In each case of nail pigmentation, an acral lentiginous melanoma must be excluded.
[Longitudinal melanonychia induced by hydroxyurea therapy]
Posted by rob on November 14, 2005 under Uncategorized |
Scientists at The Ohio State University Comprehensive Cancer Center have identified a new pathway in the progression of chronic myelogenous leukemia (CML). They also discovered that an extract from the root of a common ornamental plant can suppress the process.
The findings, appearing in the November issue of Cancer Cell, may yield new treatment options for the estimated 4,600 people in the United States who are expected to develop CML this year ? especially those with advanced disease, or those who become resistant to the drug Gleevec.
The promising new extract is forskolin, which comes from the root of the plant coleus forskohlii, a native of India that is used in the United States as an ornamental plant.
New Treatment Option For CML From Garden Plant Found Discovered By Ohio State | CMLHope.Com | Bringing Hope To CML
Posted by rob on November 13, 2005 under Uncategorized |
Scherr M, Chaturvedi A, Battmer K, Dallmann I, Schultheis B, Ganser A, Eder M
Blood. 2005 Nov 8;
Although targeting the BCR-ABL tyrosine kinase activity by imatinib mesylate (STI571) has rapidly become first line therapy in chronic myeloid leukemia (CML), drug resistance suggests that combination therapy directed to a complementing target may significantly improve treatment results. To identify such potential targets, we used lentivirus-mediated RNA interference (RNAi) as a tool for functional genomics in cell lines as well as primary normal and CML CD34+ cells. In a conditional cell culture model, we demonstrate that RNAi mediated reduction of SHP2, STAT5, and Gab2 protein expression inhibits Bcr-Abl- but not cytokine-dependent proliferation in a dose dependent manner. Similarily, colony formation of purified primary CML- but not of normal CD34+ colony-forming cells is specifically reduced by inhibition of SHP2, STAT5, and Gab2 expression, respectively. In addition, coexpression of both anti-Bcr-Abl and anti-SHP2 shRNAs from a single lentiviral vector induces stronger inhibition of colony formation as compared to either shRNA alone. The data indicate that Bcr-Abl expression may affect the function of normal signaling molecules. Targeting these molecules may harbour significant therapeutic potential for the treatment of CML.
Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML).
Posted by rob on under Uncategorized |
Bocchia M, Abruzzese E, Forconi F, Ippoliti M, Trawinska MM, Pirrotta MT, Raspadori D, Tozzi M, Gozzetti A, Lauria F
Leukemia. 2005 Nov 10;
No abstract yet.
Imatinib does not impair specific antitumor T-cell immunity in patients with chronic myeloid leukemia.
Posted by rob on under Uncategorized |
Roy L, Guilhot J, Martineau G, Guilhot F
Leukemia. 2005 Nov 10;
No abstract yet
HubMed Abstracts
Posted by rob on under Uncategorized |
Stanojkovic TP, Zizak Z, Mihailovic-Stanojevic N, Petrovic T, Juranic Z
J Exp Clin Cancer Res. 2005 Sep ; 24(3): 387-95
The present work examines the effects of beta and alpha1-adrenoceptor antagonist carvedilol, and angiotensin converting enzyme (ACE) inhibitor captopril, on in vitro growth of tumor cell lines derived from breast tumor (MDA-MB-361), melanoma (Fem-x), cervix adenocarcinoma (HeLa) and human myelogenous leukemia (K562). Carvedilol or captopril were applied on malignant cells at 0.1, 1, 5, 10 and 50 micromol. Cell survival was determined 48 hrs after drugs action by MTT. On all cell lines tested, carvedilol was a very potent inhibitor of cell proliferation. The order of sensitivity of various human cell lines to carvedilol’s antiproliferative action was: myelogenous leukemia K562 (IC50 = 22.66 +/- 2.14 micromol), > cervix carcinoma HeLa (IC50 = 30.56 +/- 5.16 micromol), > melanoma Fem-x (IC50 = 32.17 +/- 5.75 micromol), > breast tumor MDA-MB-361 (IC50 = 35.04 +/- 2.95 micromol). In contrast, captopril, used in doses from 0.1-50 micromol, was ineffective (IC50 > 50 micromol) to the same cell lines. It is important to note that captopril in concentrations > 1 micromol led to a statistically significant increase in the percent of survived melanoma Fem-x cells (p Inhibition of proliferation on some neoplastic cell lines-act of carvedilol and captopril.
Posted by rob on under Uncategorized |
Li Y, Yang L, Chen S, Zhang Y, Wu X
Hematology. 2005 Oct ; 10(5): 387-92
Understanding the clonality and restricted usage of the TCR Vbeta repertoire of expanded T-cells induced by the chronic myelogenous leukemia (CML) associated antigen may be useful in helping design new immunotherapeutic strategies specifically for CML. T-cells from cord blood that had been stimulated by different stimulators (IL-2, PHA, CML cells, K562 cells and bcr-abl peptide) were amplified in vitro by liquid T-cell culture and the mixed lymphocyte and tumor cell culture (MLTC) method. By using the RT-PCR, the CDR3 segments of 24 variable region genes of TCR beta was analyzed in T-cells from 22 cases of cord blood before and after T-cell culture, to observe the usage of TCR Vbeta repertoire. The PCR products were further labeled with fluorescence and analyzed by the Genescan technique for the CDR3 size, to evaluating clonality of the detectable TCR Vbeta T-cells. Only a part of 24 Vbeta subfamily T-cells (3-15 subfamilies) could be detected, however, all of the 24 TCR Vbeta subfamily of T-cells were detected after in vitro culture with PHA or IL-2+anti-CD3 antibody. The number of expressed TCR Vbeta subfamilies was gradually reduced by prolonging the time of culture with CML-associated antigens. The restricted expression of TCR Vbeta subfamilies and oligoclonal expansion of Vbeta21 T-cells were found in cultured T-cells induced by CML cells, K562 cells or bcr-abl peptide. In conclusion, T-cells from cord blood may have the potential capability of proliferation in different TCR Vbeta subfamily T-cells, and the ability for restricted expression and clonal expansion, when T-cells were induced by CML associated antigen.
The TCR Vbeta repertoire usage of T-cells from cord blood induced by chronic myelogenous leukemia associated antigen.
Posted by rob on under Uncategorized |
Rosato RR, Almenara JA, Maggio SC, Atadja P, Craig R, Vrana J, Dent P, Grant S
Mol Cancer Ther. 2005 Nov ; 4(11): 1772-85
Interactions between the novel histone deacetylase inhibitor LAQ824 and the cyclin-dependent kinase inhibitor roscovitine were examined in human leukemia cells. Pretreatment (24 hours) with a subtoxic concentration of LAQ824 (30 nmol/L) followed by a minimally toxic concentration of roscovitine (10 mumol/L; 24 hours) resulted in greater than additive effects on apoptosis in U937, Jurkat, and HL-60 human leukemia cells and blasts from three patients with acute myelogenous leukemia. These events were associated with enhanced conformational changes in Bax; mitochondrial release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor; and a marked increase in caspase activation. LAQ824/roscovitine-treated cells displayed caspase-dependent down-regulation of p21(CIP1) and Mcl-1 and a pronounced caspase-independent reduction in X-linked inhibitor of apoptosis (XIAP) expression. The lethality of this regimen was significantly attenuated by ectopic expression of XIAP, a nuclear localization signal-defective p21(CIP1) mutant, Mcl-1, and Bcl-2. Combined exposure to LAQ824 and roscovitine resulted in a significant reduction in XIAP mRNA levels and diminished phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Notably, roscovitine blocked LAQ824-mediated differentiation. Finally, LAQ824 and roscovitine individually and in combination triggered an increase in generation of reactive oxygen species; moreover, coadministration of the free radical scavenger N-acetylcysteine prevented LAQ824/roscovitine-mediated mitochondrial injury and apoptosis. Collectively, these findings suggest that combined treatment of human leukemia cells with LAQ824 and roscovitine disrupts maturation and synergistically induces apoptosis, lending further support for an antileukemic strategy combining novel histone deacetylase and cyclin-dependent kinase inhibitors.
Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells.
Posted by rob on under Uncategorized |
Kantarjian H
J Natl Compr Canc Netw. 2005 Nov ; 3 Suppl 1: S41-5
No abstract yet
Trends in the management of chronic myelogenous leukemia.
Posted by rob on under Uncategorized |
Ye QD, Gu LJ, Zhao YX, Zhao JC, Chen WG, Zhang B, Jiang LM
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Oct ; 13(5): 759-63
To explore the effects of tetra-arsenic tetra-sulfide (As(4)S(4)) in treatment of human chronic myelogenous leukemia K562 cells and its mechanism, trypan blue staining and microculture MTS assay were used to measure the effects of As(4)S(4) on growth inhibition of K562 cells; the morphologic change was determined by Wright’s staining assay. The apoptosis rate and cell cycle were detected by flow cytometry; the changes of transcript and protein level were determined by real-time quantitative RT-PCR and Western blot analysis, respectively. The results indicated that As(4)S(4) had signigicant cytotoxicity on K562 cells. At the concentration of 0.5 micromol/L, the cell viability decreased significantly after being cultured with As(4)S(4) for 24 hours. When the concentration was lower than 0.1 micromol/L, As(4)S(4) had a little effect on K562 cells. The effect of As(4)S(4) on K562 was time- and concentration- dependent. After being cultured with As(4)S(4) at the concentration of 1.0 micromol/L for 24 to 48 hours, K562 cells displayed typical morphological changes of apoptosis. At a concentration greater than or equal to 1.0 micromol/L, As(4)S(4) could induce apoptosis significantly. After 12 hours of incubation with 1.0 micromol/L As(4)S(4), the apoptosis rate increased from (3.47 +/- 0.42)% to (6.16 +/- 0.98%). At the same time, the percentage of cells in G(1) phase decreased from (69.65 +/- 3.24)% to (50.53 +/- 2.86)%, whereas the percentage of cells in G(2)/M phase increased from (9.56 +/- 2.51)% to (12.91 +/- 2.13)%. The mRNA level of Bcl-X(L) and the protein level of pAkt were down-regulated after the inhibition of As(4)S(4), while the mRNA expression of Bcl-2, Bad and Bax had no change. Both of the transcript and protein level of bcr-abl had no change after incubation with As(4)S(4). It is concluded that As(4)S(4) can inhibit the growth of K562 cells efficiently through inducing apoptosis and cell cycle arrest. It seems that As(4)S(4) interferes with pAkt pathway and down-regulates Bcl-X(L), which may be involved in the response of K562 to this agent.
[Apoptosis Mechanism in Human Chronic Myelogenous Leukemia K562 Cells Induced by Tetra-arsenic Tetra-sulfide.]
Posted by rob on under Uncategorized |
We have set up an interactive map where all members of the group worldwide can tag their location on the map. It takes only about a minute to register and post a message on the map for others to see.
http://www.frappr.com/cml
Posted by rob on November 8, 2005 under Uncategorized |
Th?rn I, Olsson-Str?mberg U, Ohlsen C, Jonsson AM, Klangby U, Simonsson B, Barbany G
Haematologica. 2005 Nov ; 90(11): 1471-6
BACKGROUND AND OBJECTIVES: Accurate quantification of BCR-ABL mRNA is of critical importance for managing patients with chronic myeloid leukemia (CML) who are receiving imatinib therapy. RNA degradation thus constitutes a potential problem for laboratories quantifying minimal residual disease (MRD). Patients’ samples that take a long time to be transported from the hospital to the analyzing laboratory may be subject to RNA degradation with a corresponding loss in sensitivity and possible generation of false negative results. Recently, RNA preservation systems have been developed in order to improve RNA stability. The aim of the present study was to investigate such a system. DESIGN AND METHODS: We evaluated the performance of the PAXgene Blood RNA Kit in follow-up CML peripheral blood samples and compared the results to those from unstabilized parallel Trizol extracted samples. The different sample processing methods were evaluated by real-time polymerase chain reaction (PCR) analysis. RESULTS: RNA isolated with the PAXgene system gave a superior yield per milliliter of blood than did the routine Trizol extraction method. However, although of comparable quality, the RNA did not PCR-amplify as efficiently as equal amounts of RNA from routinely processed samples. Therefore, RNA processed with the PAXgene system showed decreased sensitivity for MRD detection, resulting in false negative results. The sensitivity was comparable to that of samples processed routinely 20-30 hours after phlebotomy. INTERPRETATION AND CONCLUSIONS: We conclude that routinely processed, i.e. unstabilized, peripheral blood that reaches the laboratory and is processed within 30 hours is preferable for MRD detection. Optimal results were achieved with fresh samples processed within 5 hours with the Trizol method. However, RNA stabilization may be useful if sample transit is expected to exceed 30 hours.
The impact of RNA stabilization on minimal residual disease assessment in chronic myeloid leukemia.
Posted by rob on under Uncategorized |
Ferrand H, Tamburini J, Mouly S, Bouscary D, Bergmann JF
Clin Infect Dis. 2005 Dec 1; 41(11): 1684-5
No abstract yet
Listeria monocytogenes meningitis following imatinib mesylate-induced monocytopenia in a patient with chronic myeloid leukemia.
Posted by rob on under Uncategorized |
Tchirkov A, Couderc JL, P?rissel B, Goumy C, Regnier A, Uhrhammer N, Verrelle P, Berger M
Leukemia. 2005 Nov 3;
No abstract yet
Major molecular response to imatinib in a patient with chronic myeloid leukemia expressing a novel form of e8a2 BCR-ABL transcript.
Posted by rob on under Uncategorized |
Rumpold H, Wolf AM, Wolf D
Leukemia. 2005 Nov 3;
No abstract yet
The role of P-glycoporotein in imatinib resistance.
