Pharmacodynamic behavior of liposomal antisense oligonucleotides targeting Her-2/neu and vascular endothelial growth factor in an ascitic MDA435/LCC6 human breast cancer model.
The nature of anti-cancer therapeutics is currently undergoing a paradigm change, with biologic agents slowly being introduced into the therapeutic armory, displacing or complimenting the traditionally used cytotoxic agents. These new agents include monoclonal antibodies, recombinant DNA, antisense oligonucleotides (ASO) and others. To assess the new therapeutics, new predictive models are required. Utilizing the MDA435/LCC6 human breast cancer xenograft model, the pharmacokinetic behavior of antisense oligonucleotides targeted against vascular endothelial growth factor and HER-2/neu was assessed. For pharmacodynamic analysis, ASO in buffer or encapsulated in a liposomal formulation were injected intravenously or intraperitoneally into MDA435/LCC6 ascites tumor-bearing mice. Plasma antisense elimination, tissue distribution, total peritoneal antisense and peritoneal cell associated antisense levels were determined. Liposomal encapsulation led to significant decreases in the plasma elimination rate, as evidenced by an approximate 10-fold increase in mean AUC over 24 hours, as well as enhanced peritoneal cell delivery in mice bearing ascites tumors. Tissue distribution studies of both free and liposome encapsulated ASO indicated that ASO distribution was dictated primarily by the liposomal carrier when administered in liposomal form.
Waterhouse
Dawn N
DN
British Columbia Cancer Research Centre, Department of Advanced Therapeutics, Vancouver, BC, Canada. dwater@bccancer.bc.ca
Dragowska
Wieslawa H
WH
Gelmon
Karen A
KA
Mayer
Lawrence D
LD
Bally
Marcel B
MB
D000818:Animals; D001201:Ascites / Q000188:drug therapy* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D006801:Humans; D008081:Liposomes; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000493:pharmacokinetics*
D004268:DNA-Binding Proteins; D008081:Liposomes; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2