3 years ago

Fenretinide, Troglitazone, and Elmiron Add to Weight of Evidence Support for Hemangiosarcoma Mode-of-Action from Studies in Mice.

Koza-Taylor, Lawton, Roy, Criswell, Cook, Obert, Opsahl, Coskran, Qian, Ziemek
Pharmaceuticals and chemicals produce hemangiosarcomas (HS) in mice, often by nongenotoxic, proliferative mechanisms. A mode-of-action (MOA) for hemangiosarcoma was proposed based on information presented at an international workshop (Cohen et al., 2009). Five key elements of the MOA were articulated and included hypoxia, macrophage activation, increased angiogenic growth factors, dysregulated angiogenesis/erythropoiesis, and endothial cell proliferation. The goal of the current study was to add to the weight-of-evidence for the proposed MOA by assessing these key elements with three different compounds of varying potency for HS induction: fenretinide (high), troglitazone (intermediate), and elmiron (low). Multiple endpoints, including hypoxia (hyproxyprobe, transcriptomics), endothelial cell (EC) proliferation, and clinical and anatomic pathology, were assessed after 2, 4, and 13-weeks of treatment in B6C3F1 mice. All three compounds demonstrated strong evidence for dysregulated erythropoiesis (decrease in RBC and a failure to increase reticulocytes) and macrophage activation (4 to 11-fold increases); this pattern of hematological changes in mice might serve as an early biomarker to evaluate endothelial cell proliferation in suspected target organs for potential HS formation. Fenretinide demonstrated all five key elements, while troglitazone demonstrated four and elmiron demonstrated three. Transcriptomics provided support for the five elements of the MOA, but was not any more sensitive than hypoxyprobe IHC for detecting hypoxia. The overall transcriptional evidence for the key elements of the proposed MOA was also consistent with the potency of HS induction. These data, coupled with the previous work with 2-butoxyethanol (2-BE) and pregablin, increase the weight-of-evidence for the proposed MOA for HS formation.

Publisher URL: http://doi.org/10.1093/toxsci/kfx195

DOI: 10.1093/toxsci/kfx195

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