Antiangiogenic Treatment with Three Thrombospondin-1 Type 1 Repeats versus Gemcitabine in an Orthotopic Human Pancreatic Cancer Model

Abstract

Purpose: In this study, we investigated the antitumor efficacy of thrombospondin-1three type 1 repeats (3TSR), the antiangiogenic domain of thrombospondin-1, in comparison and in combination with gemcitabine, in an orthotopic pancreatic cancer model. Experimental Design: Human pancreatic cancer cells were injected into the pancreas of severe combined immunodeficient mice. The animals were treated with 3TSR, gemcitabine, 3TSR plus gemcitabine, or vehicle for 3 weeks. Subsequently, the effects of 3TSR and/or gemcitabine on tumor growth, tumor necrosis, microvessel density, cancer cell proliferation, apoptosis, and endothelial cell apoptosis were analyzed. Results: After 3 weeks of treatment, 3TSR reduced tumor volume by 65%, and gemcitabine by 84%. Tumor volume was not statistically different between gemcitabine group and combinatorial treatment group. Extensive necrotic areas were observed in tumors from 3TSR-treated mice, whereas tumors from gemcitabine and combinatorially treated mice were less necrotic than control tumors. 3TSR reduced tumor microvessel density and increased tumor blood vessel endothelial cell apoptosis. In contrast, gemcitabine induced apoptosis and inhibited proliferation of cancer cells. Conclusion: 3TSR, the antiangiogenic domain of thrombospondin-1, showed comparable antitumor efficacy to gemcitabine in a human pancreatic cancer orthotopic mouse model. No synergistic effect was found when the two drugs were combined and possible reasons are discussed in detail. A delicate balance between normalization and excessive regression of tumor vasculature is important when initiating alternative combinatorial regimens for treatment of patients with pancreatic cancer.

ABT-898 Induces Tumor Regression and Prolongs Survival in a Mouse Model of Epithelial Ovarian Cancer

“…Although several studies have targeted the VEGF family in ovarian cancer (15)(16)(17)(18), another effective approach for the treatment of various cancers are peptides derived from the TSR antiangiogenic domain of TSP-1 (19). Numerous studies have shown the antiangiogenic and antitumor effects of 3TSR (20)(21)(22) and ABT-510 (11,23,24) and have shown safety and efficacy in animal and human studies (12,13,25,26). We have previously evaluated ABT-510 in the treatment of EOC and reported decreased tumor burden as well as an increase in the uptake of the chemotherapy drugs cisplatin and paclitaxel through vascular normalization (8).…”

Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies

“…The schedules used are also highly variable, although typically these studies involved giving the AIAs and chemotherapeutic drugs over the same time period. What is clear is that the majority of studies reported an increased benefit of the combination approach, although in a few examples no additional benefit was found (164)(165)(166).…”

Thrombospondin-based antiangiogenic therapy

“…66 In most cases, the inhibition of tumor growth by 3TSR is due to inhibition of angiogenesis, with no direct effects on the tumor cells. However, 3TSR reportedly inhibits the growth of brain and ovarian cancer cells through direct interaction with CD36, which is expressed on the tumor cells.…”