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• W2040571102 endingPage "e65620" @default.
• W2040571102 startingPage "e65620" @default.
• W2040571102 abstract "Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third leading cause of cancer death worldwide. The only approved systemic treatment for unresectable HCC is the oral kinase inhibitor, sorafenib. Recombinant human acid sphingomyelinase (rhASM), which hydrolyzes sphingomyelin to ceramide, is an orphan drug under development for the treatment of Type B Niemann-Pick disease (NPD). Due to the hepatotropic nature of rhASM and its ability to generate pro-apoptotic ceramide, this study evaluated the use of rhASM as an adjuvant treatment with sorafenib in experimental models of HCC.In vitro, rhASM/sorafenib treatment reduced the viability of Huh7 liver cancer cells more than sorafenib. In vivo, using a subcutaneous Huh7 tumor model, mouse survival was increased and proliferation in the tumors decreased to a similar extent in both sorafenib and rhASM/sorafenib treatment groups. However, combined rhASM/sorafenib treatment significantly lowered tumor volume, increased tumor necrosis, and decreased tumor blood vessel density compared to sorafenib. These results were obtained despite poor delivery of rhASM to the tumors. A second (orthotopic) model of Huh7 tumors also was established, but modest ASM activity was similarly detected in these tumors compared to healthy mouse livers. Importantly, no chronic liver toxicity or weight loss was observed from rhASM therapy in either model.The rhASM/sorafenib combination exhibited a synergistic effect on reducing the tumor volume and blood vessel density in Huh7 xenografts, despite modest activity of rhASM in these tumors. No significant increases in survival were observed from the rhASM/sorafenib treatment. The poor delivery of rhASM to Huh7 tumors may be due, at least in part, to low expression of mannose receptors. The safety and efficacy of this approach, together with the novel findings regarding enzyme targeting, merits further investigation." @default.
• W2040571102 created "2016-06-24" @default.
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• W2040571102 date "2013-05-28" @default.
• W2040571102 modified "2023-09-26" @default.
• W2040571102 title "Recombinant Human Acid Sphingomyelinase as an Adjuvant to Sorafenib Treatment of Experimental Liver Cancer" @default.
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• W2040571102 doi "https://doi.org/10.1371/journal.pone.0065620" @default.
• W2040571102 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3665770" @default.
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