Very Interesting - Maybe It Willl Work

May 30, 2008

Combination Of Two Novel Anti-cancer Agents May Help Fight CML Resistant To

Current Therapy

ScienceDaily (May 29, 2008) - Virginia Commonwealth University Massey Cancer

Center researchers have identified that a combination of novel anti-cancer

compounds is able to kill chronic myelogenous leukemia cells previously

resistant to conventional forms of therapy.

Chronic myelogenous leukemia, or CML, is a cancer of the bone marrow caused

by a specific genetic abnormality and is one of the more common forms of

leukemia. Imatinib mesylate, or Gleevec, is a highly effective anti-cancer

agent that has revolutionized the course of therapy for patients with CML.

It works by inhibiting the activity of a mutant protein, known as Bcr/Abl,

which is responsible for the disease. However, despite initial success,

patients eventually become resistant to imatinib mesylate, often through the

development of further mutations in the Bcr/Abl protein.

According to Grant, M.D., Massey's associate director for

translational research and co-leader of the cancer center's cancer cell

biology program, and senior author of the study, resistance to imatinib

mesylate prompted the search for newer agents that are active against the

mutated forms of Bcr/Abl. Such agents include MK-0457, a Bcr/Abl kinase

inhibitor that also targets another protein called an aurora kinase. Aurora

kinase plays an important role in mitosis and cell division. In preclinical

studies, MK-0457 is active against the T315I Bcr/Abl mutation, a major cause

of imatinib resistance, and has shown promise in early clinical trials,

Grant said.

In this study, Grant and colleagues examined the effects of combining

MK-0457 with vorinostat, a novel targeted agent that has recently been

approved for the treatment of cutaneous T-cell lymphoma. They found that

this combination leads to a dramatic induction of apoptosis, or programmed

cell death in CML cells, including imatinib-resistant cells bearing the

T315I or other mutations. The article was pre-published as a First Edition

Paper in Blood, the journal of the American Society of Hematology, which

appeared online May 27.

Further, Grant said that the interaction between these agents may occur at

multiple levels, including potentiation of Bcr/Abl inhibition as well as

enhanced disruption of aurora kinase and mitosis. In addition, the group

demonstrated that vorinostat-mediated up-regulation of Bim, a pro-apoptotic

protein, contributed significantly to the effectiveness of this regimen.

" Our findings suggest it may be possible to develop a clinical regimen

combining a third-generation Bcr/Abl kinase and aurora kinase inhibitor,

such as MK-0457, with histone deacetylase inhibitors, such as vorinostat, "

Grant said.

" Theoretically, this combination could improve upon the results of Bcr/Abl

kinase inhibitors administered alone, particularly in the case of

imatinib-resistant disease, " he said. Further preclinical studies are

underway to test this hypothesis.

This work was supported by grants from the National Institutes of Health,

the Leukemia and Lymphoma Society of America, the V Foundation, and the

Department of Defense. Merck Pharmaceuticals supplied the agents tested in

the preclinical studies.

Grant, who is a professor of medicine and the Shirley and Sture

Gordon Olsson Professor of oncology, worked with a team that included: Yun

Dai, Ph.D., Shuang Chen, Ph.D., Charis A. Venditti, Xin-Yan Pei, Ph.D., and

Tri K. Nguyen, Ph.D., all in the VCU Department of Medicine; and Dent,

Ph.D., a professor in the VCU Department of Biochemistry.

_____

Adapted from materials provided by <http://www.vcu.edu> Virginia

Commonwealth University.

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Virginia Commonwealth University (2008, May 29). Combination Of Two Novel

Anti-cancer Agents May Help Fight CML Resistant To Current Therapy.

ScienceDaily. Retrieved May 30, 2008, from http://www.sciencedaily.com-

/releases/2008/05/080529124823.htm

Zavie (age 69)

67 Shoreham Avenue

Ottawa, Canada, K2G 3X3

dxd AUG/99

INF OCT/99 to FEB/00, CHF

No meds FEB/00 to JAN/01

Gleevec since MAR/27/01 (400 mg)

CCR SEP/01. #102 in Zero Club

2.8 log reduction Sep/05

3.0 log reduction Jan/06

2.9 log reduction Feb/07

3.5 log reduction Jan/08

3.6 log reduction Apr/08

e-mail: zmiller@...

Tel: 613-726-1117

Fax: 309-296-0807

Cell: 613-202-0204

ID: zaviem

YM: zaviemiller

Skype: Zavie

May 30, 2008

I know I haven't been on for a loooooonnnnng time, but I still read all the

messages....Zavie this looks very very very promising!!!!

Warm regards,

Penny

From: Zavie miller & lt;zmiller@... & gt;

Subject: [ ] Very Interesting - Maybe It Willl Work

Date: Friday, May 30, 2008, 4:12 PM