TY - JOUR
T1 - Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy
AU - Blansfield, Joseph A.
AU - Caragacianu, Diana
AU - Alexander, H. Richard
AU - Tangrea, Michael A.
AU - Morita, Shane Y.
AU - Lorang, Dominique
AU - Schafer, Peter
AU - Muller, George
AU - Stirling, David
AU - Royal, Richard E.
AU - Libutti, Steven K.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - Purpose: 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 tumor microenvironment. 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-agentt herapy. Conclusions: This combination of agents causes an in hospitable microenvironment for tumor cells and shows great promise for use in the clinic.
AB - Purpose: 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 tumor microenvironment. 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-agentt herapy. Conclusions: This combination of agents causes an in hospitable microenvironment for tumor cells and shows great promise for use in the clinic.
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U2 - 10.1158/1078-0432.CCR-07-1562
DO - 10.1158/1078-0432.CCR-07-1562
M3 - Article
C2 - 18172279
AN - SCOPUS:40749120515
SN - 1078-0432
VL - 14
SP - 270
EP - 280
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -