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Pancreatic cancer is one of the most deadly malignancies with few viable treatment options. Previously, we reported that recombinant three thrombospondin-1 type 1 repeats (3TSR), an antiangiogenic domain of thrombospondin-1, inhibited tumor growth and angiogenesis in an orthotopic human pancreatic cancer model. In this study, we investigated whether continuous administration (CA) of 3TSR was more effective than daily bolus injection, and would decrease the effective dosage. The impact of 3TSR on tumor vessel density and perfusion was also studied. Methods: One week after tumor cell implantation into the pancreas, tumor-bearing mice were randomized into 5 groups: (a) 3TSR CA via osmotic pumps, 1.5 mg/kg/day; (b) 3TSR CA, 0.75 mg/kg/day; (c) 3TSR daily ip injection, 3 mg/kg/day; (d) 3TSR daily ip injection, 0.75 mg/kg/day; (e) Control, ip injections of vehicle or implantation of vehicle-loaded pumps. Mice in all groups were sacrificed after three weeks of treatment. To evaluate the perfusion and patency of tumor blood vessels, fluorescein-labeled dextran was intravenously injected prior to sacrifice. Tumor vasculature was assessed both structurally and functionally. Results: 3TSR was biologically stable for at least 7 days in osmotic pumps implanted in mice. After 3 weeks of treatment, 3TSR daily injection at 3 mg/kg/day significantly reduced tumor volume from 664.0 ± 28.6 mm3 (control) to 387.5 ± 52.7 mm3 (P<0.01), whereas 3TSR 0.75 mg/kg/day daily injection did not significantly decrease tumor volume (573.6 ± 88.6 mm3, P=0.24 vs control). In contrast, when delivered continuously, 3TSR at both 1.5 mg/kg/day and 0.75 mg/kg/day significantly inhibited tumor growth (377.5 ± 49.4 mm3 and 392.7 ± 77.0 mm3 respectively, P<0.01 vs control), and tumor volumes of the two CA groups were comparable with that of 3TSR 3 mg/kg/day bolus injection. The anti-tumor efficacy of 3TSR was correlated with its antiangiogenic efficacy. Tumor microvessel density was 5.9% (of a 20× visual field) in control mice. 3TSR 0.75 mg/kg/day bolus injection did not significantly reduce tumor microvessel density (6.1%, P=0.58 vs control), whereas tumor microvessel density was decreased to 2.9% - 3.2% after treatment with 3TSR 3 mg/kg/day bolus injection or CA at 1.5 mg/kg/day or 0.75 mg/kg/day (P<0.01 vs control). 3TSR treatment also decreased tumor vessel patency in the same dose-response pattern. 3TSR 3 mg/kg/day bolus injection or CA at the two doses significantly reduced tumor vessel perfusion by 40%-42%, whereas 3TSR 0.75 mg/kg/day bolus injection showed little effect on tumor vessel patency. Conclusion: Continuous administration of 3TSR shifted the dose-response curve to the left and improved the potency of therapy in the orthotopic pancreatic cancer model. 3TSR also reduced tumor microvessel density and decreased the patency and blood flow of tumor vessels.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]