Designer Host Defense Peptide als neue Therapieoption bei Weichgewebssarkomen?

Abstract

Introduction: Soft tissue sarcomas are a rare and heterogeneous group of tumors. They are derived from connective tissue and comprise less than one percent of all malignancies. Currently the primary treatment approach is surgical resection optionally accompanied by radio- and chemotherapy. However the response rate of sarcomas towards chemotherapeutics is still unsatisfying. The innate immune response might play a key role in cancer development and might therefore offer a more effective option for the treatment of this cancer entity. The goal of this in vitro and in vivo study was to analyse the oncolytic effect of a novel host defense–like lytic peptide in human sarcoma cell lines. Methods and Materials: In vitro a human lipo- (SW872) and synovialsarcoma (SW982) cell line, and primary human fibroblasts were exposed to [D]-K₃H₃L₉, a short 15-mer D,L-amino acid peptide (exposure time: 24 hours, dose: 0 μM to 100 μM). Morphological changes were controlled microscopically. Cell vitality (MTT-assay) and proliferation (BrdU-assay) were quantified and the LD₅₀ was determined. In vivo SW872 and SW982 cells (5 × 10⁶ cells/mouse) were injected subcutaneously into athymic nude mice. When the mean tumor volume reached 216 mm₃ (SW872) or 138 mm₃ (SW982), the peptide was administered intratumorally 3 times per week (single dose: 8.5 mg/kg) for 3 weeks with one subsequent follow-up week. Histological and immunohistochemical analyses were performed afterwards. Results: In vitro [D]-K₃H₃L₉ significantly (p < 0.05) inhibited cell metabolism in a dose dependent manner. The mean LD₅₀ was reached at a peptide concentration of 52 μM (SW872) and 24 μM (SW982). Microscopic findings confirmed these results. In comparison to the control group the tumor volume of the treatment group significantly decreased. In the SW872 tumors a complete remission could be shown macroscopically in 43 % of cases. The histological and immunohistochemical analysis demonstrated a significant decrease of proliferation and an increase of the necrotic area in the treatment group. Conclusion: In summary, [D]-K₃H₃L₉ exerts very promising potent oncolytic activity on lipo- and synovialsarcoma cells in vitro and in vivo. Thus HDPs may offer a novel therapeutic option in the treatment of soft tissue sarcomas.