Thalidomide Inspires a New Approach to Treating Cancer

Researchers at the U.S. National Cancer Institute (NCI, Bethesda, MD, USA) and Celgene Corporation (Summit, NJ, USA) tested both separately and in combination the drugs lenalidomide (an immunomodulatory drug), sunitinib (a tyrosine kinase inhibitor), and low-dose metronomic cyclophosphamide for their abilities to inhibit endothelial cell tube formation, rat aortic ring outgrowth, tumor growth, and metastatic development in mice. In addition, ectopic tumor lysates were evaluated for the presence of proangiogenic proteins.

The results showed that the three agents alone each significantly inhibit endothelial cells' ability to form tubes, and significantly inhibit the multicellular microenvironment in the rat aortic ring assay. This effect was also significantly augmented when the agents were combined. Furthermore, the three-drug combination was able halt the progression of tumor growth almost completely in xenograft models of ocular melanoma, colon cancer, pancreatic cancer, and cutaneous melanoma. The drugs significantly decreased the number of proliferating cells in tumors, significantly increased the number of cells undergoing active cell death in tumors, and significantly decreased the number of blood vessels in treated tumors. The study was published in the January 1, 2008, issue of Clinical Cancer Research.

"Combination therapy shows a decrease in the compensatory up-regulation of proangiogenic proteins after treatment when compared with single-agent therapy,” concluded lead author Joseph Blansfield, M.D., of the NCI, and colleagues. "This combination of agents causes an inhospitable microenvironment for tumor cells and shows great promise for use in the clinic.”

Lenalidomide is a new form of the drug thalidomide, which was banned in the early 1960's after it was found to cause deformed limbs in the children of women who took it early in pregnancy. Thalidomide has shown activity in numerous dermatologic, infectious, and autoimmune disorders, including ulcerations and wasting syndromes related to HIV infection, Behçet's disease, cutaneous lesions of systemic lupus erythematosus, sarcoidosis, and chronic graft-versus-host disease. The drug's antiangiogenic properties led to early testing in a variety of types of cancer, and the drug has showed promising antineoplastic activity in multiple myeloma, Kaposi's sarcoma, mantle-cell lymphoma, and idiopathic myelofibrosis.

In May 2006, thalidomide received approval by the U.S. Food and Drug Administration (FDA) for primary treatment of multiple myeloma in combination with dexamethasone.


Related Links:
U.S. National Cancer Institute
Celgene Corporation