The combination of the tyrosine kinase receptor inhibitor SU6668 with paclitaxel affects ascites formation and tumor spread in ovarian carcinoma xenografts growing orthotopically.

PURPOSE: The purpose of this study was to investigate the antitumor activity of SU6668, tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), fibroblast growth factor receptor 1 (FGFR1), and platelet-derived growth factor receptor beta (PDGFRbeta), as single-agent therapy and in combination with paclitaxel on ovarian carcinoma xenograft models transplanted in the peritoneal cavity of nude mice. EXPERIMENTAL DESIGN: HOC22 and HOC79 ascites-producing human ovarian carcinoma xenografts were transplanted i.p. into nude mice. SU6668 was given p.o. (200 mg/kg, daily) as a single agent or in combination with paclitaxel i.v. (6 mg/kg/dose every other day or 20 mg/kg/dose weekly). Tumor burden was evaluated at the end of the treatment period as ascites volume and tumor cells, VEGF, FGF-2, and PDGF levels in ascites, and involvement of the organ of the peritoneal cavity. Response was evaluated as percentage increment of life span (%ILS). RESULTS: SU6668 affected ascites formation and tumor burden in the peritoneal cavity of nude mice bearing HOC22 and HOC79 xenografts. Decreased levels of VEGF and PDGF in ascites paralleled this effect. The overall survival of the mice bearing HOC xenograft (HOC79 less response than HOC22) was significantly increased by the treatment with SU6668. The magnitude of the effects depended on the length of treatment and tumor burden at the beginning of treatment. The combination of SU6668 with paclitaxel significantly prolonged the survival of mice bearing HOC79, compared with single therapies. SU6668-based combination therapy was more effective with paclitaxel given at the optimal dose and schedule (20 mg/kg every 7 days for 3 doses) than at the same total dose but split (6 mg/kg every 2 days for 10 doses). However, a similar outcome was observed when giving high-dose paclitaxel (20 mg/kg every 7 days for 3 doses) in monotherapy or split low-dose paclitaxel (6 mg/kg every 2 days for 10 doses) but in combination with SU6668. The addition of paclitaxel, by either schedule, to SU6668 treatment inhibited tumor spread in the peritoneal organs (omentum, pancreas, and diaphragm) even at low doses of paclitaxel. A greater effect was observed with prolonged treatments. CONCLUSIONS: This study shows that SU6668 in combination with paclitaxel inhibits ovarian carcinoma progression in the peritoneal cavity, by blocking ascites formation and tumor spread. Because an adequate schedule and dose of the combination might be as effective as conventional chemotherapy, this should be considered as a therapeutic alternative. These findings provide a rationale for the clinical evaluation of combination therapies affecting multiple biological targets in this tumor type.

SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer.

The purpose of this study was to evaluate the activity of the indolinone kinase inhibitor SU11248 against the receptor tyrosine kinase KIT in vitro and in vivo, examine the role of KIT in small cell lung cancer (SCLC), and anticipate clinical utility of SU11248 in SCLC. SU11248 is an oral, multitargeted tyrosine kinase inhibitor with direct antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, KIT, and FLT3 receptors. Treatment of the KIT-expressing SCLC-derived NCI-H526 cell line in vitro with SU11248 resulted in dose-dependent inhibition of stem cell factor-stimulated KIT phosphotyrosine levels and proliferation. The biological significance of KIT inhibition was evaluated in vivo by treating mice bearing s.c. NCI-H526 tumors with SU11248 or another structurally unrelated KIT inhibitor, STI571 (Gleevec), which is also known to inhibit Bcr-Abl and PDGFRbeta. SU11248 treatment resulted in significant tumor growth inhibition, whereas inhibition from STI571 treatment was less dramatic. Both compounds reduced phospho-KIT levels in NCI-H526 tumors, with a greater reduction by SU11248, correlating with efficacy. Likewise, phospho-PDGFRbeta levels contributed by tumor stroma and with known involvement in angiogenesis were strongly inhibited by SU11248 and less so by STI571. Because platinum-based chemotherapy is part of the standard of care for SCLC, SU11248 was combined with cisplatin, and significant tumor growth delay was measured compared with either agent alone. These results expand the profile of SU11248 as a KIT signaling inhibitor and suggest that SU11248 may have clinical potential in the treatment of SCLC via direct antitumor activity mediated via KIT as well as tumor angiogenesis via vascular endothelial growth factor receptor FLK1/KDR and PDGFRbeta.