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PDGF Signaling in Non-oncological Indications

The rationale for PDGF signaling antagonists in non-oncological indications, such as vasculoproliferative disease, is linked to the upregulation of PDGF signaling in smooth muscle cells derived from atherosclerotic vessels, as well as from neointima lesions (Ross et al. 1990; Tanizawa et al. 1996; Ueda et al. 1996; Rubin et al. 1998). In animal models of restenosis, significant efficacy has been obtained either with neutralizing antibodies to PDGF or with different types of inhibitory approaches (Ferns et al. 1991; Myl-larniemi et al. 1997; Sirois et al. 1997; Banai et al. 1998; Bilder et al. 1999; Giese et al. 1999; Hart et al. 1999; Yamasaki et al. 2001; Bilder et al. 2003). Although these studies are encouraging and have indicated that PDGF antagonists might be useful clinically for the treatment of vasculoproliferative diseases, there are some concerns as to whether inhibition of PDGF signaling alone will be sufficiently efficacious for the treatment atherosclerotic lesions that usually involve multiple pathways and cells (Sihvola et al. 1999; Kozaki et al. 2002; Sihvola 2003).

Reduced cell proliferation, collagen synthesis, and deposition have been observed in bleomycin-induced fibrosis with PDGFR antagonists like AG1296 or by expressing a soluble form of the PDGFRb (Rice et al. 1999; Yoshida et al. 1999). Treatment of glomerulonephritis with either STI571 or PDGF aptamers led to a significant reduction in mesangial cell proliferation and collagen deposition preventing renal scarring, suggesting a therapeutic potential of PDGF antagonists in fibrotic conditions (Floege and Ostendorf 2001).

Last but not least, stimulation of PDGF signaling was found to contribute to increased interstitial fluid pressure (IFP) in experimental tumors (Pietras et al. 2001, 2002, 2003). Therefore, inhibition of PDGF signaling, with STI571 or other antagonists, may be useful in lowering the intra-tumoral fluid pressure, facilitating an increased uptake of cytotoxic drugs in tumors that result in an improved therapeutic efficacy.

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