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


METHODS
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.
Garofalo
Angela
A
Department of Oncology, Mario Negri Institute for Pharmacological Research, 24125 Bergamo, Italy.
Naumova
Elitza
E
Manenti
Luigi
L
Ghilardi
Carmen
C
Ghisleni
Gabriele
G
Caniatti
Mario
M
Colombo
Tina
T
Cherrington
Julie M
JM
Scanziani
Eugenio
E
Nicoletti
Maria Ines
MI
Giavazzi
Raffaella
R
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D000078183:Oxindoles; D017239:Paclitaxel / Q000008:administration & dosage*; D011422:Propionates; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C412603:orantinib; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel