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Plant derivative attacks the roots of leukemia

23-Feb-2005 - A daisy-like plant known as Feverfew or Bachelor's Button, found in gardens across North America, is the source of an agent that kills human leukemia stem cells like no other single therapy, scientists at the University of Rochester Medical Center's James P. Wilmot Cancer Center have discovered. Their investigation is reported in the online edition of the journal, Blood.

It will take months before a useable, pharmaceutical compound can be made from parthenolide, the main component in Feverfew. However, UR stem cell expert Craig T. Jordan, Ph.D., and Monica L. Guzman, Ph.D., lead author on the Blood paper, say their group is collaborating with University of Kentucky chemists, who have identified a water-soluble molecule that has the same properties as parthenolide.

The National Cancer Institute has accepted this work into its rapid access program, which aims to move experimental drugs from the laboratory to human clinical trials as quickly as possible.

"This research is a very important step in setting the stage for future development of a new therapy for leukemia," says Jordan. "We have proof that we can kill leukemia stem cells with this type of agent, and that is good news."

Parthenolide is the first single agent known to act on myeloid leukemia at the stem-cell level, which is significant because current cancer treatments do not strike deep enough to kill mutant cells where the malignancy is born.

In other words, even the most progressive leukemia treatment, a relatively new drug called Gleevec, is effective only to a degree. It does not reach the stem cells, so "you're pulling the weed without getting to the root," Jordan says.

Feverfew has been used for centuries as an herbal remedy to reduce fevers and inflammation, to prevent migraine headaches, and to ease symptoms from arthritis. (A person with leukemia, however, would not be able to take enough of the herbal remedy to halt the disease.)

Investigating stem cells that give rise to cancer is an urgent new initiative, as is identifying stem-cell treatments that might end the disease process. Jordan and Guzman are among only a handful of stem cell biologists nationwide who are specifically studying cancer stem cells. In recent years, scientists have identified cancer stems cells in blood cancers and in brain and breast tumors although the idea that cancer stems cells exist has been around for at least 40 years.

In the current study, the UR group began investigating Feverfew after other scientists showed that it prevented some skin cancers in animal models. Intrigued by the plant's anti-tumor activities, the UR team analyzed how a concentrated form of parthenolide would act on the most primitive types of acute myelogenous leukemia cells, chronic myelogenous leukemia cells and normal cells.

In laboratory experiments, they also compared how human leukemia stem cells reacted to parthenolide, versus a common chemotherapy drug called cytarabine. The result: parthenolide selectively killed the leukemia cells while sparing the normal cells better than cytarabine.

Scientists believe parthenolide might also make cancer more sensitive to other anti-tumor agents. And, the UR group was able to demonstrate the molecular pathways that allow parthenolide to cause apoptosis, or cancer cell death, increasing the chances of developing a new therapy.

Jordan is director of the Translational Research for Hematologic Malignancies program at the Wilmot Cancer Center and associate professor of Medicine and Biomedical Genetics. Guzman is senior instructor of hematology/oncology.

Other co-investigators include: Randall Rossi, associate scientist; Lilliana Karnischky, laboratory technician; Xiaojie Li, technical associate; Derick Peterson, Ph.D., assistant professor of biostatistics, and Dianna Howard, M.D., at the University of Kentucky Medical Center.

Contact: Leslie White
[email protected]
585-273-1119
University of Rochester Medical Center

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Their research is sponsored by grants from the Leukemia and Lymphoma Society, American Cancer Society and National Cancer Institute

REVLIMID(R) New Drug Application Submitted to FDA for Review

Clinical Data From Phase II Trial (MDS-003) in Patients With Myelodysplastic Syndromes With 5q Deletion Chromosomal Abnormality Submitted

SUMMIT, N.J., April 8 /PRNewswire-FirstCall/ -- Celgene Corporation (Nasdaq: CELG) announced that it has completed the rolling submission of its New Drug Application (NDA) for REVLIMID (lenalidomide), an investigational drug, to the Division of Oncology Drug Products at the U.S. Food and Drug Administration (FDA) for review. The Company's NDA is seeking approval to market REVLIMID as a treatment for transfusion-dependent patients with myelodysplastic syndromes (MDS) with a 5q deletion chromosomal abnormality.

MDS is a malignant disorder of blood cell production that affects approximately 300,000 people worldwide. The most common clinical manifestation associated with MDS is refractory anemia, and the multiple complications that stem from frequent blood transfusions. Celgene's lead IMiD(R) (Immunomodulatory drug), REVLIMID has received both orphan drug status and fast track designation from the U.S. Food and Drug Administration (FDA) and orphan drug status from the European Agency for the Evaluation of Medicinal Products for the treatment of MDS.

"Celgene appreciates and acknowledges the efforts of all those who made this filing possible, including: the more than 400 patients who participated in these MDS studies, and the international community of clinical investigators who have helped us get to this stage in the regulatory process." said Jerome B. Zeldis, M.D., Ph.D., Chief Medical Officer and VP, Medical Affairs of Celgene Corporation.

About REVLIMID(R)

REVLIMID is a member of a new class of novel immunomodulatory drugs, or IMiDs(R). Celgene is evaluating treatments with REVLIMID for a broad range of hematology and oncology conditions, including; multiple myeloma, the malignant blood cell disorders known as myelodysplastic syndromes (MDS) as well as solid tumor cancers. REVLIMID affects multiple intracellular biological pathways. The IMiD pipeline, including REVLIMID, is covered by a comprehensive intellectual property estate of U.S. and foreign issued and pending patent applications including composition-of-matter and use patents.

REVLIMID(R) (lenalidomide) is not approved by the FDA or any other regulatory agencies as a treatment in any indication and is currently being evaluated in clinical trials for efficacy and safety for future regulatory applications.

About Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a group of hematologic malignancies that affect approximately 300,000 people worldwide. Myelodysplastic syndromes occur when blood cells remain in an immature or "blast" stage within the bone marrow and never develop into mature cells capable of performing their necessary functions. Eventually, the bone marrow may be filled with blast cells suppressing normal cell development. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed each year in the United States, with mean survival rates ranging from approximately six months to six years for the different classifications of MDS. MDS patients must often rely on blood transfusions to manage symptoms of anemia and fatigue until they develop life-threatening iron overload and/or toxicity, thus underscoring the critical need for new therapies targeting the cause of the condition rather than simply managing its symptoms.

About 5q Deletion Chromosomal Abnormality

Chromosomal (cytogenetic) abnormalities are detected in more than half of patients with myelodysplastic syndrome (MDS), and involve a deletion in all or part of one or more specific chromosomes. The most common cytogenetic abnormalities in MDS are deletions in the long arm of chromosomes 5, 7, and 20. Another common abnormality is an extra copy of chromosome 8. A deletion involving the 5q chromosome may be involved in 20 to 30% of all MDS patients. The World Health Organization has also recently identified a unique subset of MDS patients with a "5q- Syndrome" where the only chromosomal abnormality is a specific portion of the 5q chromosome.

About Celgene

Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit the Company's website at http://www.celgene.com .

This release contains certain forward-looking statements which involve known and unknown risks, delays, uncertainties and other factors not under the Company's control, which may cause actual results, performance or achievements of the Company to be materially different from the results, performance or other expectations implied by these forward-looking statements. These factors include results of current or pending research and development activities, actions by the FDA and other regulatory authorities, and those factors detailed in the Company's filings with the Securities and Exchange Commission such as 10K, 10Q and 8K reports.

CONTACT:
Robert J. Hugin
Senior VP and CFO
+1-908-673-9102

Brian P. Gill
Director PR-IR
Celgene Corporation
+1-908-673-9530

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