Antitumor and antimetastatic activity of ribozymes targeting the messengerRNA of vascular endothelial growth factor receptors

Chemically stabilized hammerhead ribozymes are nuclease-resistant, RNA-base d oligonucleotides that selectively bind and cleave specific target RNAs, D ue to their potential for specifically inhibiting gene expression, ribozyme s are being investigated for therapeutic applications as well as for the el ucidation of gene function. In particular, we have investigated ribozymes t hat target the mRNA of the vascular endothelial growth factor (VEGF) recept ors because VEGF signaling is an important mediator of tumor angiogenesis a nd metastasis, Here we report pharmacodynamic studies testing anti-Flt-1 (V EGFR-1) and anti-KDR (VEGFR-2) ribozymes in animal models of solid tumor gr owth 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 i n a statistically significant and dose-dependent inhibition of lung metasta sis in this model. The anti-Flt-1 ribozyme was then tested in a xenograft m odel 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 r educed the growth and metastasis of solid tumors in vivo.