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

To: tuck who wrote (2866)	6/5/2007 12:52:23 PM
From: tom pope	Respond to of 3044

ML: Seeking new angles for Velcade Wrapping up ASCO with subcu Velcade and doxil combo data Two final presentations of note at ASCO included data from a small study comparing subcutaneous to intravenous administration of Velcade, which we find intriguing, and the phase III data that recently lead to the expansion of Velcade’s label to include combination use with Doxil in relapsed/refractory multiple myeloma. Maintain estimates and Neutral. Small study compares subcutaneous to I.V. Velcade Data was presented from a 24-patient randomized trial comparing subcutaneous with intravenous administration of Velcade at 1.3 mg/m2 twice weekly. Patients received a median of 5 cycles in both arms and response rates were the same for the two groups at 42%. While PK/PD data showed the Cmax (maximum plasma concentration) higher in the subcu arm, the bioavailability (AUC, area under the curve) was comparable. After speaking with the company and investigators at ASCO, it is unclear whether subcutaneous administration will ultimately show comparable clinical benefit, but Millennium plans to confer with the FDA and quickly develop plans for a larger trial. We view the potential prospect of a more patient friendly subcu Velcade attractive, though the potential impact on physician practices and economics will also have to be considered. [abstract #8046] Velcade + Doxil phase III data with superior TTP presented Velcade’s label was recently expanded to include use in combination with Doxil (a pegylated liposomal formulation of doxorubicin), which is sold by Ortho Biotech (Millennium’s co-promote partner), for the treatment of relapsed/refractory multiple myeloma. The phase III data leading to the expanded label was presented at ASCO and showed a 43% improvement in TTP (time to progression), 9.3 months for Velcade + Doxil vs. 6.5 months for Velcade alone. Having another approved regimen for Velcade and extra incentive for Ortho Biotech in the co-marketing arrangement are positive developments, but whether they impact sales remains to be seen and we maintained our models on the label expansion. [abstract #8002].

To: tuck who wrote (2866)	6/5/2007 3:27:47 PM
From: Icebrg	Respond to of 3044

Unclear to me what is meant by (-)-gossypol. Does the double negative mean just gossypol, or what? I've seen this in genetic studies, where it means the gene in question was entirely (both alleles) knocked out, but I don't understand it in this context. Illumination appreciated. It is not minus minus but minus hyphen. (–)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-XL-mediated apoptosis resistance Christopher L. Oliver1, Michelle B. Miranda2, Sanjeev Shangary2, Stephanie Land3, Shaomeng Wang5 and Daniel E. Johnson2,4 Departments of 1 Otolaryngology, 2 Medicine, 3 Biostatistics, and 4 Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania and 5 Departments of Internal Medicine and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan Requests for reprints:Christopher L. Oliver, Department of Otolaryngology University of Pittsburgh Eye and Ear, 200 Lothrop Street, Suite 500 Pittsburgh, PA 15213-2546. Phone: 412-647-2110; Fax: 412-647-2080. E-mail: olivercl{at}msx.upmc.edu Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family, including Bcl-2 and Bcl-XL, contributes to malignant transformation and subsequent resistance to traditional chemotherapeutics. Thus, these proteins represent attractive targets for novel anticancer agents. The small molecule, gossypol, was initially investigated as a contraceptive agent, but subsequently has been shown to possess anticancer properties in vitro and in vivo. Recently gossypol has been found to bind to Bcl-XL and, with less affinity, to Bcl-2. Here we investigate the ability of the (–) enantiomer of gossypol, (–)-gossypol, to overcome the apoptosis resistance conferred by Bcl-2 or Bcl-XL overexpression in Jurkat T leukemia cells. (–)-Gossypol potently induced cell death in Jurkat cells overexpressing Bcl-2 (IC50, 18.1 ± 2.6 µmol/L) or Bcl-XL (IC50, 22.9 ± 3.7 µmol/L). Vector-transfected control cells were also potently killed by (–)-gossypol (IC50, 7.0 ± 2.7 µmol/L). By contrast, the chemotherapy drug etoposide only induced efficient killing of vector-transfected cells (IC50, 9.6 ± 2.3µmol/L). Additionally, (–)-gossypol was more efficient than etoposide at inducing caspase-3 activation and phosphatidylserine externalization in the setting of Bcl-2 or Bcl-XL overexpression. (–)-Gossypol-induced apoptosis was associated with Bak activation and release of cytochrome c from mitochondria, suggesting a mitochondrial-mediated apoptotic mechanism. Moreover, (–)-gossypol treatment of isolated mitochondria purified from Bcl-2-overexpressing cells also resulted in cytochrome c release, indicating a possible direct action on Bcl-2 present in the mitochondrial outer membrane. Taken together, these results suggest that (–)-gossypol is a potent and novel therapeutic able to overcome apoptosis resistance by specifically targeting the activity of antiapoptotic Bcl-2 family members. (–)-Gossypol may be a promising new agent to treat malignancies that are resistant to conventional therapies.