Pharmacodynamic Behavior of Liposomal Antisense Oligonucleotides Targeting Her-2/neu and Vascular Endothelial Growth Factor in an Ascitic MDA435/LCC6 Human Breast Cancer Model

Abstract

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.

The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling

“…The sensitization of VSM cells to the loss of CYGB was completely abrogated upon pre-treatment with the pan-caspase inhibitor z-VAD-fmk. There was also a fraction of STS-induced cytotoxicity, which was insensitive to z-VAD-fmk as previously shown in other systems 25 (Figure 6D). Most importantly, over-sensitization to cell death following CYGB silencing was inhibited by the antioxidant N-acetyl cysteine (NAC) (Figure 6D) and occurrence of apoptosis was confirmed by showing that cleaved caspase-3 was increased upon silencing of CYGB and treatment with STS (Figure 6E).…”

Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth

“…When comparing the control animals to the ILKAS-treated animals, the tumor size in the ILKAS-treated group was significantly lower (Po0.05) at all measured time points. None of the mice treated with the ILKAS displayed signs of toxicity, and the ILKAS dose used was consistent with previous studies from our laboratory using antisense therapeutics (Hu et al, 2003;Waterhouse et al, 2004).…”

Reactive Self-Assembly of Polymers and Proteins to Reversibly Silence a Killer Protein

“…The extent of cell death was measured in HeLa cells treated with increasing doses of the nanogel conjugates (Figure 8). Staurosporine, a protein kinase inhibitor known to induce apoptosis 41 was used as a positive control. After 24 hours, cell viability was measured using an Alamar Blue assay.…”