Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors.
Chemically stabilized hammerhead ribozymes are nuclease-resistant, RNA-based oligonucleotides that selectively bind and cleave specific target RNAs. Due to their potential for specifically inhibiting gene expression, ribozymes are being investigated for therapeutic applications as well as for the elucidation of gene function. In particular, we have investigated ribozymes that target the mRNA of the vascular endothelial growth factor (VEGF) receptors because VEGF signaling is an important mediator of tumor angiogenesis and metastasis. Here we report pharmacodynamic studies testing anti-Flt-1 (VEGFR-1) and anti-KDR (VEGFR-2) ribozymes in animal models of solid tumor growth and metastasis. Ribozymes targeting either Flt-1 or KDR significantly inhibited primary tumor growth in a highly metastatic variant of Lewis lung carcinoma. However, only treatment with the anti-Flt-1 ribozyme resulted in a statistically significant and dose-dependent inhibition of lung metastasis in this model. The anti-Flt-1 ribozyme was then tested in a xenograft model of human metastatic colorectal cancer in which significant inhibition of liver metastasis was observed. Taken together, these data represent the first demonstration that synthetic ribozymes targeting VEGF receptor mRNA reduced the growth and metastasis of solid tumors in vivo.
Pavco
P A
PA
Ribozyme Pharmaceuticals Inc, Boulder, Colorado 80301, USA. pavco@rpi.com
Bouhana
K S
KS
Gallegos
A M
AM
Agrawal
A
A
Blanchard
K S
KS
Grimm
S L
SL
Jensen
K L
KL
Andrews
L E
LE
Wincott
F E
FE
Pitot
P A
PA
Tressler
R J
RJ
Cushman
C
C
Reynolds
M A
MA
Parry
T J
TJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D016337:RNA, Catalytic / Q000235:genetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016337:RNA, Catalytic; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor