Simultaneous targeting of VEGF message and VEGF receptor signaling as a therapeutic anticancer approach.
BACKGROUND
Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis.


METHODS
Antisense phosphorothiolate oligodeoxynucleotides (PS-ODNs) were used to reduce VEGF production while the small molecule PD0203359-0002 (PD203359) was used to inhibit VEGF/bFGF receptor tyrosine kinase activity.


RESULTS
PD203359 exposure was found to profoundly impair the growth of human endothelial cells (HMVEC-L) at doses 20-fold less than those affecting human renal cell carcinoma (Caki-1) cell growth. In vivo, treatment with PD203359 inhibited tumor cell-induced angiogenesis and resulted in a significant tumor growth delay. Treatment with VEGF antisense PS-ODNs also significantly increased the time for tumors to grow to five times the starting size. Most importantly, when the PD203359 and VEGF antisense treatments were combined, a greater antitumor response than could be achieved with either therapy alone was observed.


CONCLUSIONS
Simultaneously targeting VEGF production and VEGF receptor signaling enhances the anticancer efficacy of either therapy alone.
Shi
Wenyin
W
Department of Radiation Oncology, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA. wshi@ufl.edu
Siemann
Dietmar W
DW
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D016376:Oligonucleotides, Antisense; D009946:Organothiophosphorus Compounds; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor