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  • Title: Inhibition of Kaposi's sarcoma in vivo by fenretinide.
    Author: Ferrari N, Morini M, Pfeffer U, Minghelli S, Noonan DM, Albini A.
    Journal: Clin Cancer Res; 2003 Dec 01; 9(16 Pt 1):6020-9. PubMed ID: 14676128.
    Abstract:
    PURPOSE: We examined the effects of fenretinide [N-(4-hydroxyphenyl)retinamide; (4HPR)] on highly angiogenic Kaposi's sarcoma tumors in vivo and investigated the mechanisms involved for potential clinical applications. EXPERIMENTAL DESIGN: (CD-1)BR nude mice bearing KS-Imm cell tumors were randomized to receive 4HPR or vehicle until sacrifice. In vitro, KS-Imm and endothelial cells were treated with 4HPR to study the effects on proliferation, apoptosis, migration, and invasion; in vivo angiogenesis was evaluated in the Matrigel model. Angiogenesis-related and retinoid receptor molecules were examined at the mRNA and protein expression levels. RESULTS: In vivo, 4HPR significantly (P<0.001) reduced growth of detectable Kaposi's sarcoma (KS) xenografts and inhibited angiogenesis in the Matrigel plug assay (P<0.04). In vitro, 4HPR affected KS-Imm and endothelial cell growth and KS-Imm migration and invasion. 4HPR invasion inhibition was associated with decreased release of matrix metalloprotease-2 and rapid reduction of vascular endothelial growth factor (VEGF) expression by KS cells and of vascular endothelial growth factor receptor 2 (VEGFR2) by KS and endothelial cells. Finally, 4HPR repression of angiogenesis was associated with a 4HPR-induced increase in retinoic acid receptor beta expression. CONCLUSIONS: These data indicate that 4HPR inhibits KS tumor growth in vivo through a mechanism involving the modulation of angiogenesis-associated growth factors and their receptors on both tumor and endothelial cells. In addition, 4HPR inhibited invasion by decreasing of matrix metalloprotease-2 activity. Our results justify further studies to evaluate the utility of 4HPR as a chemopreventive or therapeutic agent in KS, a malignancy associated with immune suppression that has a high risk of recurrence with highly active antiretroviral therapy failure.
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