Ribozyme pharmacokinetic screening for predicting pharmacodynamic dosing regimens.
A significant amount of research has been devoted to the chemical stabilization of synthetic ribozymes, in part, so that applications to systemic disease can be explored. A nuclease-stabilized synthetic hammerhead ribozyme, ANGIOZYME, has been developed which targets the mRNA encoding a vascular endothelial growth factor receptor, Flt-1. Because the stimulation of this receptor may contribute to tumor neovascularization and subsequent tumor growth and metastasis, we have explored the systemic use of ANGIOZYME to down regulate this receptor in a syngeneic model of metastatic cancer. We describe here the application of pharmacokinetic analysis to the selection of a dosing regimen for pharmacodynamic screening in this murine cancer model. These studies demonstrate that the appropriate application of pharmacokinetic analysis is necessary for the optimization of systemic pharmacodynamic studies using synthetic ribozymes.
Parry
T J
TJ
Human Genome Sciences, Inc, Rockville, MD 20850, USA.
Bouhana
K S
KS
Blanchard
K S
KS
Pavco
P A
PA
Sandberg
J A
JA
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018995:Myosin Heavy Chains; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics; D024501:Nonmuscle Myosin Type IIB; D020871:RNA Stability; D016337:RNA, Catalytic / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1
D020533:Angiogenesis Inhibitors; C121301:Angiozyme; D016326:Extracellular Matrix Proteins; D016337:RNA, Catalytic; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains