Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

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

To: Icebrg who wrote (2050)	3/26/2004 12:43:23 PM
From: tuck	Respond to of 3044

[Bortezomib and Flavopiridol against imatinib-resistant CML] >>Blood. 2004 Mar 23 [Epub ahead of print] Bortezomib and Flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Dai Y, Rahmani M, Pei XY, Dent P, Grant S. Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA, USA. Interactions between the CDK (cyclin-dependent kinase) inhibitor Flavopiridol and the proteasome inhibitor Bortezomib were examined in Bcr/Abl(+) human leukemia cells. Co-exposure of K562 or LAMA84 cells to subtoxic concentration of Flavopiridol (150-200nM) and Bortezomib (5-8nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in NF-kappaB/DNA binding activity, enhanced phosphorylation of SEK1/MKK4, JNK, and p38 MAPK, down-regulation of Bcr/Abl, and a marked reduction in STAT3 and STAT5 activity. In imatinib-resistant K562 cells displaying increased Bcr/Abl expression, Bortezomib/Flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and Bcl-xL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl, but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/Bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of Flavopiridol to promote Bortezomib-mediated Bcr/Abl downregulation and apoptosis was mimicked by the P-TEFb inhibitor DRB. Finally, the Bortezomib/Flavopiridol regimen also potently induced apoptosis in Bcr/Abl(-) human leukemia cells. Collectively, these findings suggest that a strategy combining Flavopiridol and Bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies.<< Cheers, Tuck

To: Icebrg who wrote (2050)	3/31/2004 7:19:30 AM
From: PCSS	Read Replies (1) \| Respond to of 3044

FYI - could move MLNM (+/-) today: MLNM (IL/N): GS call 3/31 @10AM on cancer pipeline The Goldman Sachs 'In Your Office' Conference Call series will continue March 31 at 10AM with Millennium Pharmaceuticals' Dr. David Schenkein, Vice President, Oncology Clinical Development.

To: Icebrg who wrote (2050)	3/31/2004 10:19:58 AM
From: Icebrg	Read Replies (1) \| Respond to of 3044

Combined proteasome and histone deacetylase inhibition in non-small cell lung cancer. Denlinger CE, Keller MD, Mayo MW, Broad RM, Jones DR. J Thorac Cardiovasc Surg. 2004 Apr;127(4):1078-86. OBJECTIVE: Inhibitors of histone deacetylases are potent inducers of cell-cycle arrest and apoptosis in certain malignancies. We have previously demonstrated that chemotherapy activates the antiapoptotic transcription factor nuclear factor kappaB in non-small cell lung cancer and fails to induce significant levels of apoptosis. We hypothesize that nuclear factor kappaB inhibition with the proteasome inhibitor bortezomib (formerly known as PS-341) will sensitize non-small cell lung cancer cells to histone deacetylase inhibitor-mediated apoptosis. METHODS: Tumorigenic non-small cell lung cancer cells (A549, H358, and H460) were treated with bortezomib, followed by the histone deactylase inhibitor sodium butyrate. After treatment, nuclear factor kappaB transcriptional activity was measured by using a luciferase reporter assay and transcription of the nuclear factor kappaB-dependent gene IL8. Apoptosis was determined on the basis of caspase-3 activation and DNA fragmentation. Western blot analyses for the cell-cycle regulatory proteins p21 and p53 were performed, and cell-cycle alterations were determined by means of FACS analysis. Experiments were performed in triplicate, and statistical significance was determined by using unpaired t tests. RESULTS: Butyrate increased nuclear factor kappaB transcriptional activity 4-fold relative to that seen in control cells (P =.05) in all non-small cell lung cancer cell lines. Treatment with bortezomib reduced butyrate-induced activation of nuclear factor kappaB to baseline levels. The proteins p21 and p53 were stabilized after treatment with bortezomib, correlating with a G(2)/M cell-cycle arrest. Treatment with butyrate alone resulted in minimal apoptosis, but combined histone deacetylase and proteasome inhibition increased apoptosis 3- to 4-fold (P =.02). CONCLUSIONS: Combined molecular targeting of histone deacteylases and proteasomes synergistically induced apoptosis in non-small cell lung cancer. Pharmacologic nuclear factor kappaB suppression through proteasome inhibition, followed by treatment with histone deacetylase inhibitors, might represent a novel treatment strategy for patients with non-small cell lung cancer.