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: tuck who wrote (2399)	6/1/2005 4:15:02 PM
From: scaram(o)uche	Respond to of 3044

synergy, synergy...... slowly but surely, we're turning the corner against a variety of malignancies.......

To: tuck who wrote (2399)	6/3/2005 1:13:22 PM
From: tuck	Read Replies (1) \| Respond to of 3044

[More on TRAIL and Velcade: bladder and prostate cancer] >>Cancer Res. 2005 Jun 1;65(11):4902-8. Bortezomib Abolishes Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance via a p21-Dependent Mechanism in Human Bladder and Prostate Cancer Cells. Lashinger LM, Zhu K, Williams SA, Shrader M, Dinney CP, McConkey DJ. Departments of Cancer Biology and Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines that induces apoptosis in some tumor cells but not in normal cells. Unfortunately, many human cancer cell lines are refractory to TRAIL-induced cell death, and the molecular mechanisms underlying resistance are unclear. Here we report that TRAIL resistance was reversed in human bladder and prostate cancer cell lines by the proteasome inhibitor bortezomib (PS-341, Velcade). Synergistic induction of apoptosis occurred within 4 to 6 hours in cells treated with TRAIL plus bortezomib and was associated with accumulation of p21(WAF-1/Cip-1) (p21) and inhibition of cyclin-dependent kinase (cdk) activity. Roscovitine, a specific cdk1/2 inhibitor, also sensitized cells to TRAIL. Silencing p21 expression reduced levels of DNA fragmentation by 50% in cells treated with bortezomib and TRAIL, confirming that p21 was required for the response. Analysis of the TRAIL pathway revealed that caspase-8 processing was enhanced in a p21-dependent fashion in cells exposed to TRAIL and bortezomib as compared with cells treated with TRAIL alone. Thus, all downstream components of the pathway (Bid cleavage, cytochrome c release, and caspase-3 activation) were amplified. These data strongly suggest that p21-mediated cdk inhibition promotes TRAIL sensitivity via caspase-8 activation and that TRAIL and bortezomib should be combined in appropriate in vivo models as a possible approach to solid tumor therapy.<< Millenium needs to find a combination that works well, and reasonably quickly, in order to get back to double digits (or Integrilin has to start a growth trend again). TRAIL and Velcade doses are pretty well established, so perhaps this could be developed relatively quickly? Is there any reason not to start some PI trials? Cheers, Tuck