Angiogenesis in the peritoneal cavity arising from ovarian cancer leads to peritoneal carcinomatosis, malignant ascites formation, morbidity and high mortality. Recent studies in our laboratory have shown albendazole (ABZ) to be a potent inhibitor of angiogenesis and malignant ascites formation. The current study was designed to find the pharmacokinetics of the drug and its major metabolites albendazole sulfoxide (ABZSO) and albendazole sulfone (ABZSO(2)) in an experimental model of ovarian cancer. Additionally, we sought to investigate if the cancer-induced changes in the peritoneal cavity would affect the kinetics of ABZ. On this basis, ABZ was administered 150 mg/kg intraperitoneally to groups of mice bearing peritoneal carcinomatosis and also to groups of healthy mice with no tumor. Blood and peritoneal wash samples were collected for up to 72 h. Concentration of ABZ and its metabolites in the samples were analysed by an established high performance liquid chromatography method. In the healthy mice, drug and metabolite concentrations were found to be low to undetectable. On the contrary, tumor-bearing mice had higher levels of ABZSO in both the plasma and their peritoneal wash. This may at least in part be attributed to the high vascular endothelial growth factor levels present in the peritoneal cavity of the diseased mice. The data obtained in this study suggest that peritoneal carcinomatosis changes ABZ absorption from the peritoneal cavity.
[Show abstract][Hide abstract] ABSTRACT: Block copolymers were prepared via RAFT polymerization with P(PEGMEMA) as the hydrophilic block to form micelles for the controlled delivery of ABZ. The group contribution method was used to estimate the partial solubility parameters for ABZ and various polymers as potential core-forming block to achieve optimum compatibility. Different ratios between MMA and LMA, a non-compatible monomer, were prepared. Cytotoxicity tests revealed a high toxicity of the ABZ-loaded micelle resulting in 80% cell deaths at a micelle concentration of 10 µg · mL(-1) . Cellular uptake of micelles has been studied using fluorescently labeled micelles, showing that a large fraction of micelles is readily taken up by OVCAR-3 cells. RGD-conjugated micelles were prepared and showed an increased cellular uptake.
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer, and despite treatment advances, patient prognosis remains poor. During routine animal studies, we serendipitously observed that fenbendazole, a benzimidazole antihelminthic used to treat pinworm infection, inhibited brain tumor engraftment. Subsequent in vitro and in vivo experiments with benzimidazoles identified mebendazole as the more promising drug for GBM therapy. In GBM cell lines, mebendazole displayed cytotoxicity, with half-maximal inhibitory concentrations ranging from 0.1 to 0.3 µM. Mebendazole disrupted microtubule formation in GBM cells, and in vitro activity was correlated with reduced tubulin polymerization. Subsequently, we showed that mebendazole significantly extended mean survival up to 63% in syngeneic and xenograft orthotopic mouse glioma models. Mebendazole has been approved by the US Food and Drug Administration for parasitic infections, has a long track-record of safe human use, and was effective in our animal models with doses documented as safe in humans. Our findings indicate that mebendazole is a possible novel anti-brain tumor therapeutic that could be further tested in clinical trials.
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