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

To: Ian@SI who wrote (2602)	1/19/2006 6:23:20 PM
From: tuck	Respond to of 3044

[Perifosine augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced MM cell cytotoxicity] It also sings "Happy Birthday." >>Blood. 2006 Jan 17; [Epub ahead of print] Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, Podar K, Munshi NC, Chauhan D, Richardson PG, Anderson KC. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Perifosine is a synthetic novel alkylphospholipid, a new class of anti-tumor agents which targets cell membranes and inhibits Akt activation. Here we show that baseline phosphorylation of Akt in MM cells is completely inhibited by Perifosine in a time- and dose-dependent fashion, without inhibiting phosphoinositide-dependent protein kinase 1 phosphorylation. Perifosine induces significant cytotoxicity in both MM cell lines and patient MM cells resistant to conventional therapeutic agents. Perifosine does not induce cytotoxicity in peripheral blood mononuclear cells. Neither exogenous IL-6 nor IGF-1 overcomes Perifosine-induced cytotoxicity. Importantly, Perifosine induces apoptosis even of MM cells adherent to bone marrow stromal cells. Perifosine triggers JNK activation, followed by caspase-8/9 and poly (ADP)-ribose polymerase cleavage. Inhibition of JNK abrogates Perifosine-induced cytotoxicity, suggesting that JNK plays an essential role in Perifosine-induced apoptosis. Interestingly, phosphorylation of ERK is increased by Perifosine; conversely, MEK inhibitor synergistically enhances Perifosine-induced cytotoxicity in MM cells. Furthermore, Perifosine augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced MM cell cytotoxicity. Finally, Perifosine demonstrates significant antitumor activity in a human plasmacytoma mouse model, associated with downregulation of Akt phosphorylation in tumor cells. Taken together, our data provide the rationale for clinical trials of Perifosine to improve patient outcome in MM.<< Cheers, Tuck