Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: Implications for combination treatment with photodynamic therapy

Angiogenesis, the formation of new blood vessels from an existing vasculatu re, is requisite for tumor growth. It entails intercellular coordination of endothelial and tumor cells through angiogenic growth factor signaling. In terruption of these events has implications in the suppression of tumor gro wth. PD166285, a broad-spectrum receptor tyrosine kinase (RTK) inhibitor, a nd PD173074, a selective FGFR(1)TK inhibitor, were evaluated for their anti -angiogenic activity and anti-tumor efficacy in combination with photodynam ic therapy (PDT). To evaluate the anti-angiogenic and anti-tumor activities of these compounds, RTK assays, in vitro tumor cell growth and microcapill ary formation assays, in vivo murine angiogenesis and anti-tumor efficacy s tudies utilizing RTK inhibitors in combination with photodynamic therapy we re performed. PD166285 inhibited PDGFR-beta-, EGFR-, and FGFR(1)TKs and c-s rc TK by 50% (IC50) at concentrations between 7-85nM. PD173074 displayed se lective inhibitory activity towards FGFR(1)TK at 26nM. PD173074 demonstrate d (> 100 fold) selective growth inhibitory action towards human umbilical v ein endothelial cells compared with a panel of tumor cell lines. Both PD166 285 and PD173074 (at 10nM) inhibited the formation of microcapillaries on M atrigel-coated plastic. In vivo anti-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 of angiogenesis. Agains t a murine mammary 16c tumor, significantly prolonged tumor regressions wer e achieved with daily p.o. doses of PD166285 (5-10 mg/kg) or PD173074 (30-6 0 mg/kg) following PDT compared with PDT alone (p < 0.001). Many long-term survivors were also noted in combination treatment groups. PD166285 and PD1 73074 displayed potent anti-angiogenic and anti-tumor activity and prolonge d the duration of anti-tumor response to PDT. Interference in membrane sign al transduction by inhibitors of specific RTKs (e.g. FGFR(1)TK) should resu lt in new chemotherapeutic agents having the ability to limit tumor angioge nesis and regrowth following cytoreductive treatments such as PDT.