title: Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  This combination of agents causes an inhospitable microenvironment for tumor cells and shows great promise for use in the clinic.
authors.affiliation: Tumor Angiogenesis Section, Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. jblansfield1@geisinger.edu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Blansfield
authors.forename: Diana
authors.initials: D
authors.lastname: Caragacianu
authors.forename: H Richard
authors.initials: HR
authors.lastname: Alexander
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tangrea
authors.forename: Shane Y
authors.initials: SY
authors.lastname: Morita
authors.forename: Dominique
authors.initials: D
authors.lastname: Lorang
authors.forename: Peter
authors.initials: P
authors.lastname: Schafer
authors.forename: George
authors.initials: G
authors.lastname: Muller
authors.forename: David
authors.initials: D
authors.lastname: Stirling
authors.forename: Richard E
authors.initials: RE
authors.lastname: Royal
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003520:Cyclophosphamide / Q000008:administration & dosage; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D000077269:Lenalidomide; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage; D051381:Rats; D000077210:Sunitinib; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D011758:Pyrroles; D013792:Thalidomide; D003520:Cyclophosphamide; D000077269:Lenalidomide; D000077210:Sunitinib