Augmentation of radiation response with the vascular targeting agent ZD6126.
OBJECTIVE
To examine the antivascular and antitumor activity of the vascular targeting agent ZD6126 in combination with radiation in lung and head-and-neck (H and N) cancer models. The overall hypothesis was that simultaneous targeting of tumor cells (radiation) and tumor vasculature (ZD6126) might enhance tumor cell killing.


METHODS
A series of in vitro studies using human umbilical vein endothelial cells (HUVEC) and in vivo studies in athymic mice bearing human lung (H226) and H and N (squamous cell carcinoma [SCC]1, SCC6) tumor xenografts treated with ZD6126 and/or radiation were performed.


RESULTS
ZD6126 inhibited the capillary-like network formation in HUVEC. Treatment of HUVEC with ZD6126 resulted in cell cycle arrest in G2/M, with decrease of cells in S phase and proliferation inhibition in a dose-dependent manner. ZD6126 augmented the cell-killing effect of radiation and radiation-induced apoptosis in HUVEC. The combination of ZD6126 and radiation further decreased tumor vascularization in an in vivo Matrigel angiogenesis assay. In tumor xenografts, ZD6126 enhanced the antitumor activity of radiation, resulting in tumor growth delay.


CONCLUSIONS
These preclinical studies suggest that ZD6126 can augment the radiation response of proliferating endothelial H and N and lung cancer cells. These results complement recent reports suggesting the potential value of combining radiation with vascular targeting/antiangiogenic agents.
Hoang
Tien
T
Hematology/Oncology Division, Ohio State University College of Medicine, Columbus, OH, USA.
Huang
Shyhmin
S
Armstrong
Eric
E
Eickhoff
Jens C
JC
Harari
Paul M
PM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy*; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003094:Collagen; D003131:Combined Modality Therapy / Q000379:methods; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D007797:Laminin; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D011509:Proteoglycans; D011897:Random Allocation; D016196:S Phase / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D020169:Caspases