Anti-Angiogenic Activity of Selected ReceptorTyrosine Kinase Inhibitors, PD166285 and PD173074:Implications for Combination Treatment withPhotodynamic Therapy

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• 作者：Dimitroff ; Charles J. ; Klohs ; Wayne ; Sharma ; Amarnath ; Pera ; Paula ; Driscoll ; Denise ; Veith ; Jean ; Steinkampf ; Randall ; Schroeder ; Mel ; Klutchko ; Sylvester ; Sumlin ; Adam ; Henderson ; Barbara ; Dougherty ; Thomas J. ; Bernacki ; Ra
• 关键词：angiogenesis ; cytostatic chemotherapy ; tyrosine kinase ; inhibitors
• 刊名：Investigational New Drugs
• 出版年：1999
• 出版时间：1999
• 年：1999
• 卷：17
• 期：2
• 页码：121-135
• 全文大小：270 KB

文摘

Angiogenesis, the formation of new blood vessels from anexisting vasculature, is requisite for tumor growth. It entailsintercellular coordination of endothelial and tumor cells throughangiogenic growth factor signaling. Interruption of these eventshas implications in the suppression of tumor growth. PD166285, abroad-spectrum receptor tyrosine kinase (RTK) inhibitor, andPD173074, a selective FGFR$\_1$TK inhibitor, were evaluatedfor their anti-angiogenic activity and anti-tumor efficacy incombination with photodynamic therapy (PDT). To evaluate theanti-angiogenic and anti-tumor activities of these compounds, RTKassays, in vitro tumor cell growth and microcapillaryformation assays, in vivo murine angiogenesis andanti-tumor efficacy studies utilizing RTK inhibitors in combinationwith photodynamic therapy were performed. PD166285 inhibitedPDGFR-β-, EGFR-, and FGFR$\_1$TKs and c-src TK by50% (IC$\_50$) at concentrations between7−85nM. PD173074 displayed selective inhibitory activitytowards FGFR$\_1$TK at 26nM. PD173074 demonstrated (>100fold) selective growth inhibitory action towards human umbilicalvein endothelial cells compared with a panel of tumor cell lines.Both PD166285 and PD173074 (at 10nM) inhibited the formation ofmicrocapillaries on Matrigel-coated plastic. In vivoanti-angiogenesis studies in mice revealed that oral administration(p.o.) of either PD166285 (1−25 mg/kg) or PD173074(25−100 mg/kg) generated dose dependent inhibition ofangiogenesis. Against a murine mammary 16c tumor, significantlyprolonged tumor regressions were achieved with daily p.o. doses ofPD166285 (5−10 mg/kg) or PD173074 (30−60 mg/kg)following PDT compared with PDT alone (p<0.001). Many long-termsurvivors were also noted in combination treatment groups. PD166285and PD173074 displayed potent anti-angiogenic and anti-tumoractivity and prolonged the duration of anti-tumor response to PDT. Interference in membrane signal transduction by inhibitors ofspecific RTKs (e.g. FGFR$\_1$TK) should result in newchemotherapeutic agents having the ability to limit tumorangiogenesis and regrowth following cytoreductive treatments suchas PDT.