Antivascular therapy of oral tongue squamous cell carcinoma with PTK787.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is an important mediator in tumor vascularization, growth, and metastasis. We investigated whether blockade of the VEGF receptor (VEGF-R) signaling pathway by the tyrosine kinase inhibitor PTK787 combined with CPT-11, a semisynthetic camptothecin analogue, can inhibit the tumor growth and angiogenesis of squamous cell carcinoma of the oral tongue in an orthotopic nude mouse model.


METHODS
JMAR human oral squamous cell carcinoma cells were injected into the tongues of nude mice. Seven days later, the mice were randomized to receive a placebo, daily oral PTK787, weekly CPT-11 injection, or PTK787 plus CPT-11. After 4 weeks of treatment, the mice underwent necropsy, and the tongue tumors, cervical lymph nodes, and lungs were removed for immunohistochemical analyses.


RESULTS
CPT-11, PTK787, and PTK787 plus CPT-11 significantly decreased tumor volumes and prolonged survival. The combination treatment group had the most significant decrease in volume and increase in survival. PTK787 alone or in combination with CPT-11 reduced the phosphorylation of VEGF-R in tumor cells and tumor-associated endothelial cells, was associated with decreased microvessel density, a decreased proliferative index, and an increased apoptotic index. PTK787 alone or the combination therapy resulted in apoptosis of both tumor cells and tumor-associated endothelial cells.


CONCLUSIONS
These results suggest that targeting VEGF-R tyrosine kinase activity can be an effective therapeutic approach in squamous cell carcinoma of the oral tongue.
Yazici
Yasemin D
YD
Department of Head and Neck Surgery, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kim
Seungwon
S
Jasser
Samar A
SA
Wang
Zhuoying
Z
Carter
Kenny B
KB
Bucana
Corazan D
CD
Myers
Jeffrey N
JN
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D066298:In Vitro Techniques; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010793:Phthalazines / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D014062:Tongue Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D010793:Phthalazines; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D000077146:Irinotecan; D002166:Camptothecin