Targeting the platelet-derived growth factor receptor in antivascular therapy for human ovarian carcinoma

Purpose: We sought to determine whether blockade of platelet-derived growth factor receptor (PDGF-R) activation by oral administration of a PDGF-R tyrosine kinase inhibitor (ST1571) alone or in combination with i.p. paclitaxel can inhibit the progression of tumors caused by human ovarian carcinoma cells growing in the peritoneal cavity of female nude mice. Experimental Design: In several different experiments, paclitaxel-sensitive and paclitaxel-resistant metastatic human ovarian carcinoma cells were injected into the peritoneal cavity of nude mice. Seven days later, groups (n = 10) of mice began receiving a control treatment, ST1571 alone, paclitaxel alone, or a combination of ST1571 and paclitaxel. The mice were necropsied after 45 days of treatment. Results: Treatment with combination therapy significantly reduced tumor weight (relative to control or single-agent therapy) in all three human ovarian cancer cell lines. Immunohistochemical analyses revealed that PDGF-R activation was blocked by ST1571 administered alone or in combination with paclitaxel. Tumor-associated endothelial cells expressed both PDGF-R and phosphorylated PDGF-R. In mice receiving combination therapy, tumor-associated endothelial cells underwent apoptosis, leading to decreases in microvessel density and tumor cell proliferation relative to control and single-agent therapy. Conclusions: These results show that administration of a PDGF-R tyrosine kinase inhibitor in combination with paclitaxel impairs the progression of ovarian cancer in the peritoneal cavity of nude mice, in part, by blockade of PDGF, an endothelial cell survival factor, which results in the increased apoptosis of tumor-associated endothelial cells.