Block of AIDS-Kaposi's sarcoma (KS) cell growth, angiogenesis, and lesion formation in nude mice by antisense oligonucleotide targeting basic fibroblast growth factor. A novel strategy for the therapy of KS.

Abstract

Kaposi's sarcoma (KS) is the most frequent tumor of HIV-1-infected individuals (AIDS-KS). Typical features of KS are proliferating spindle-shaped cells, considered to be the tumor cells of KS, and endothelial cells forming blood vessels. Basic fibroblast growth factor (bFGF), a potent angiogenic factor, is highly expressed by KS spindle cells in vivo and after injection in nude mice it induces vascular lesions closely resembling early KS in humans. Similar lesions are induced by inoculating nude mice with cultured spindle cells from AIDS-KS lesions (AIDS-KS cells) which produce and release bFGF. Here we show that phosphorothioate antisense (AS) oligonucleotides directed against bFGF mRNA (ASbFGF) inhibit both the growth of AIDS-KS cells derived from different patients and the angiogenic activity associated with these cells, including the induction of KS-like lesions in nude mice. These effects are due to the block of the production of bFGF which is required by AIDS-KS cells to enter the cell cycle and which, after release, mediates angiogenesis. The effects of ASbFGF are specific, dose dependent, achieved at low (0.1-1 ,uM), nontoxic, oligomer concentrations, and are reversed by the addition of bFGF to the cells, suggesting that ASbFGF oligomers are promising drug candidates for KS therapy. (J. Clin. Invest. 1994.

Anti-tumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor

“…In the previous reports, tumor suppression by inhibition of FGFs has been achieved using: ( a) a neutralizing antibody against FGF -2, 22,23 ( b ) antisense oligonucleotides against FGF -2, 24 (c ) antisense RNA for FGF -2, 25 (d ) antisense FGF -2 DNA, 26 and ( e) anti -FGF chemicals such as carboxymethyl benzylamide dextran. 27 Our results are consistent with those findings.…”

Mechanism of Paclitaxel Activity in Kaposi’s Sarcoma

“…In this system KSC induce formation of angioproliferative lesions of mouse cell origin closely resembling human early KS (2)(3)(4). By using this model, we found that paclitaxel promotes regression of KS lesions in vivo.…”

“…Primary spindle cell cultures derived from AIDS-KS lesions (KS6, KS8, and KS12 strains; passages 8 -12) were derived and cultured as already described (2,4,6,56,57). Lesional spindle cells are latently infected by HHV-8 in vivo but lose the virus upon culture in vitro (58).…”

“…In this report we investigated the mechanism(s) of paclitaxel activity in KS by utilizing a model of experimental KS that is induced in nude mice by the s.c. inoculation of primary KS spindle cells (KSC) derived from human KS lesions (3,4,55). In this system KSC induce formation of angioproliferative lesions of mouse cell origin closely resembling human early KS (2)(3)(4).…”

Interactions between endothelial cells and HIV-1

“…However, neutralizing anti-basic FGF antibodies or antisense oligodeoxynucleotides do not totally block lesion formation after inoculation of KS cells in mice [155] and injection of basic FGF alone does not induce the edema characteristic of KS [74]. This suggests involvement of other factors.…”