Clin Cancer Res. 2008 Jan 1;14(1):270-80.
Blansfield JA, Caragacianu D, Alexander HR 3rd, Tangrea MA, Morita SY, Lorang D, Schafer P, Muller G, Stirling D, Royal RE, Libutti SK.
Angiogenesis Section, Surgery Branch, National Cancer Institute, NIH,
Bethesda, Maryland 20892, USA.
Over the past 60 years, cytotoxic chemotherapy has targeted the cancer
cell. Despite this, there have been few cancer cures. A new approach to
cancer therapy is to target the multicellular biological entity of the
EXPERIMENTAL DESIGN: Lenalidomide, an
immunomodulatory drug, sunitinib, a tyrosine kinase inhibitor, and
low-dose metronomic cyclophosphamide, were tested alone and in
combination 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.
RESULTS: The three agents
alone were shown to significantly inhibit endothelial cells' ability to
form tubes and significantly inhibit the multicellular microenvironment
in the rat aortic ring assay (P < 0.01 and P < 0.001). 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.
These agents significantly decrease the number of proliferating cells
in tumors, significantly increase the number of cells undergoing active
cell death in tumors, and significantly decrease the number of blood
vessels in treated tumors (P < 0.05). Combination therapy shows a
decrease in the compensatory up-regulation of proangiogenic proteins
after treatment when compared with single-agent therapy.
This combination of agents causes an inhospitable microenvironment for
tumor cells and shows great promise for use in the clinic.