Alert Number 46
Date: October 4, 2004
In a recent Topics Alert (Number 45) we discussed the recall of Vioxx, Merck's billion dollar drug. Vioxx was the direct competitor of Celebrex, the other major COX-2 inhibitor on the market.
The other thing that has been very interesting about Celebrex has been its reputation for killing cancer cells. In fact, it has done well in clinical trials for some varieties of colon cancer, and is being looked at for other cancers. Now comes a very interesting article from Ohio State, discussing a variation of Celebrex, a slightly modified molecule that seems to have much higher cancer fighting abilities, independent of the COX-2 inhibition. I like that since I was beginning to worry whether the problems with Vioxx had to do with COX-2 inhibition in the first place and would therefore affect the entire class.
I read this article from beginning to end (write to us if you want to locate a full text copy). While it is still in pre-clinical stage, the lab work thus far sounds quite promising. This is one more of the small molecule drugs, similar to those that we discussed in a recent article titled Target Mitochondrion, discussing the mitochondrial pathway of killing cancer cells. I am encouraged by these new initiatives. Hopefully we will see clinical trial announcements soon. It appears that this Celebrex look-alike has the backing of the NCI, which might help get it off the ground.
Blood. 2004 Sep 28 [Epub ahead of print]
A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma via a caspase and Bcl-2 independent mechanism.
Johnson AJ, Smith LL, Zhu J, Heerema NA, Jefferson S, Mone A, Grever M, Chen CS, Byrd JC.
Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Chronic lymphocytic leukemia (CLL) is an incurable adult leukemia characterized by disrupted apoptosis. OSU03012 is a bioavailable third generation celecoxib derivative devoid of cyclooxygenase-2 inhibitory activity that potently induces apoptosis in prostate cancer cell lines and is being developed as an anti-cancer therapy in the NCI Rapid Access to Interventional Therapy (RAID). We assessed the ability of OSU03012 to induce cytotoxicity in primary CLL cells and the mechanism by which this occurs. The LC50 (lethal concentration 50%) of OSU03012 at 24 hours was 7.1 micro M and this decreased to 5.5 micro M at 72 hours. Additionally, we have demonstrated that OSU03012 mediates apoptosis by activation of the intrinsic, mitochondrial pathway of apoptosis but also activates alternative cell death pathways that are caspase independent. The early activation of both caspase dependent and independent pathways of apoptosis is novel to OSU03012 and suggests it has great potential promise for the treatment of CLL. Moreover, unlike the great majority of therapeutic agents utilized to treat leukemia or other forms of cancer, OSU03012 induces apoptosis entirely independent of bcl-2 expression. Overall, these data provide justification for further pre-clinical development of OSU03012 as a potential therapeutic agent for CLL.
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