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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (2398)	6/1/2005 2:51:09 PM
From: tuck	Read Replies (2) \| Respond to of 3044

>>Clinical Cancer Research Vol. 11, 4259-4265, June 1, 2005 Cooperative Cytotoxicity of Proteasome Inhibitors and Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand in Chemoresistant Bcl-2-Overexpressing Cells Alessio Nencioni1,2, Lucia Wille1, Giovanna Dal Bello2, Davide Boy2, Gabriella Cirmena2, Sebastian Wesselborg3, Claus Belka4, Peter Brossart5, Franco Patrone2 and Alberto Ballestrero2 Authors' Affiliations: 1 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; 2 Department of Internal Medicine, University of Genova, Genova, Italy; and Departments of 3 Internal Medicine I, 4 Radiation Oncology, and 5 Hematology, Oncology and Immunology, University of Tubingen, Tubingen, Germany Requests for reprints: Alessio Nencioni, Department of Internal Medicine, University of Genova, V.le Benedetto XV 6, 16132 Genova, Italy. Phone: 39-10-353-8990; Fax: 39-10-353-8650; E-mail: A.Nencioni@gmx.net. Purpose: Bcl-2 overexpression is frequently detected in lymphoid malignancies, being associated with poor prognosis and reduced response to therapy. Here, we evaluated whether Bcl-2 overexpression affects the cytotoxic activity of proteasome inhibitors taken alone or in association with conventional anticancer drugs or tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Experimental Design: Jurkat cells engineered to overexpress Bcl-2 were treated with proteasome inhibitors (MG132, epoxomicin, and bortezomib), anticancer drugs (etoposide and doxorubicin), TRAIL, or combinations of these compounds. Cell death and loss of mitochondrial transmembrane potential were detected by flow cytometry. Cytosolic relocalization of cytochrome c and SMAC/Diablo, caspase cleavage, and Bcl-2 and Mcl-1 levels were determined by immunoblotting. Nuclear factor-B inhibition was done by retroviral transduction with a dominant-negative mutant of IB. Results: Bcl-2 overexpression results in significant inhibition of apoptosis in response to proteasome inhibitors, antiblastics, and TRAIL. Addition of TRAIL to proteasome inhibitors results in a synergistic cytotoxic effect in Bcl-2-overexpressing cells, whereas this result is not reproduced by the combination of proteasome inhibitors with antiblastic drugs. Importantly, proteasome inhibitors plus TRAIL induce mitochondrial dysfunction irrespective of up-regulated Bcl-2. Bcl-2 cleavage to a fragment with putative proapoptotic activity and elimination of antiapoptotic Mcl-1 may both play a role in proteasome inhibitors-TRAIL cooperation. Conversely, nuclear factor-B inhibition by proteasome inhibitors is per se insufficient to explain the observed synergy. Conclusions: Combined proteasome inhibitors and TRAIL overcome the apoptotic threshold raised by Bcl-2 and may prove useful in the treatment of chemoresistant malignancies with up-regulated Bcl-2.<< Cheers, Tuck

To: Icebrg who wrote (2398)	6/2/2005 2:34:31 PM
From: Ian@SI	Read Replies (1) \| Respond to of 3044

More from Ken Anderson on Velcade... Public release date: 2-Jun-2005 Contact: Bill Schaller william_schaller@dfci.harvard.edu 617-632-5357 Dana-Farber Cancer Institute Novel combination overcomes drug-resistant myeloma cells Researchers eager to test laboratory findings in patient trials BOSTON--A novel strategy devised by Dana-Farber Cancer Institute scientists has proved highly effective in killing drug-resistant multiple myeloma cells in the laboratory and could open a new form of attack on the deadly blood cancer, they report. Highly encouraged by the findings, the researchers hope to move rapidly to clinical trials of the therapy, a combination of the drug Velcade and an experimental compound that was designed by researchers at the Broad Institute of Massachusetts Institute of Technology and Harvard University. The report, which will be posted online this week by the Proceedings of the National Academy of Sciences (http://www.pnas.org/papbyrecent.shtml), demonstrates that the combination was more than twice as effective as either drug alone in killing resistant cells from patients' bone marrow. The promise is particularly exciting, scientists say, because many patients don't respond to Velcade, a drug approved just two years ago that's been an important new therapy for multiple myeloma, a disease which caused an estimated 11,000 deaths in 2004, according to the Multiple Myeloma Research Foundation. "This is not just another drug, this is a whole new approach to treating multiple myeloma," said Kenneth Anderson, MD, senior author of the paper, whose lead author is Teru Hideshima, MD, also of Dana-Farber. Others include Stuart L. Schreiber, PhD, of Harvard University and the Broad Institute, and Jay Bradner, MD, of Dana-Farber and the Broad Institute. Velcade is the first in a class of so-called proteasome inhibitors, which cause lethal stress in cancer cells by blocking the proteasome, a disposal mechanism that rids the cell of abnormal proteins. Cells in which the proteasome is jammed eventually commit suicide, triggered by the accumulation of proteins, explains Anderson, who is also the Kraft Family Professor of Medicine at Harvard Medical School. However, many cancer cells are resistant to proteasome inhibitors like Velcade. Recent studies have revealed an alternative protein-disposal complex, the aggresome, that may take over enough of the job when the proteasome falters to allow the cells to survive. Therefore, the Dana-Farber researchers suggested that blocking both protein disposals at once might get around this resistance mechanism. Scientists led by Schreiber at the Broad Institute designed a drug, tubacin, that blocks histone deacetylase 6, an enzyme that is critical to the aggresome's ability to function. These highly promising results, wrote the researchers, "provide the framework for clinical trials designed to enhance sensitivity and overcome resistance to bortezomib [Velcade], thereby improving patient outcome in multiple myeloma." ### The research was supported in part by grants from the National Institutes of Health, the Doris Duke Charitable Foundation, and the Multiple Myeloma Research Foundation. Dana-Farber Cancer Institute 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), a designated comprehensive cancer center by the National Cancer Institute.

To: Icebrg who wrote (2398)	1/19/2006 6:26:57 PM
From: tuck	Respond to of 3044

[PI/II trial for relapsed or refractory MM with melphalan & velcade] >>J Clin Oncol. 2006 Jan 17; [Epub ahead of print] Phase I/II Trial Assessing Bortezomib and Melphalan Combination Therapy for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma. Berenson JR, Yang HH, Sadler K, Jarutirasarn SG, Vescio RA, Mapes R, Purner M, Lee SP, Wilson J, Morrison B, Adams J, Schenkein D, Swift R. Oncotherapeutics Inc; Institute for Myeloma & Bone Cancer Research, West Hollywood; Pacific Shores Medical Group, Glendale; Cedars-Sinai Medical Center, Los Angeles, CA, Millennium Pharmaceuticals Inc; and Infinity Pharmaceuticals, Cambridge, MA. PURPOSE: Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients. METHODS: Bortezomib was administered from 0.7 to 1.0 mg/m(2) on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4. RESULTS: Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade >/= 3 toxicities were related mostly to myelosuppression. Among the 15 patients with grade 1/2 neuropathy at baseline, it resolved during treatment in one, worsened in four, and remained stable in 10 patients. Eight other patients developed grade 1/2 neuropathy during the study. CONCLUSION: Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.<< Cheers, Tuck