Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma

Abstract

Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(D,L-lactide-co-glycolide) polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth. A mouse resection model of oral carcinoma was developed by establishing tumor growth in the oral cavity by ultrasound-guided injection of 1 million SCC-9 cells in the floor of the mouth. Following resection, mice were allocated into four groups with the following treatment: 1) no treatment, 2) implanted scaffolds without diclofenac, 3) implanted scaffolds loaded with diclofenac, and 4) diclofenac given orally. Small animal ultrasound and magnetic resonance imaging were utilized for longitudinal determination of tumor recurrence. At the end of 7 weeks following tumor resection, 33% of mice with diclofenac-loaded scaffolds had a recurrent tumor, in comparison to 90%–100% of the mice in the other three groups. At this time point, mice with diclofenac-releasing scaffolds showed 89% survival rate, while the other groups showed survival rates of 10%–25%. Immunohistochemical staining of recurrent tumors revealed a near 10-fold decrease in the proliferation marker Ki-67 in the tumors derived from mice with diclofenac-releasing scaffolds. In summary, the local application of diclofenac in an orthotopic mouse tumor resection model of oral cancer reduced tumor recurrence with significant improvement in survival over a 7-week study period following tumor resection. Local drug release of anti-inflammatory agents should be investigated as a therapeutic option in the prevention of tumor recurrence in oral squamous carcinoma.

Keywords:

• tumor recurrence
• oral squamous cell carcinoma
• head and neck cancer
• NSAIDs
• drug releasing polymers
• mouse model

Acknowledgments

The authors are grateful to Gabriele Trompke, Gisela Refrath, and Gabi Neßenius for their excellent technical assistance. Financial support was provided by the research grant from the state of Schleswig-Holstein and the European Union ERDF-European Regional Development Fund (MOIN CC, Zukunftsprogramm Wirtschaft) and by the medical faculty of UK-SH, Campus Kiel (Faculty Grant, NP), Sonderforschungsbereich 877 (SFB 877), and the Kreitz Stiftung (NP and ST).

Disclosure

The authors report no conflicts of interest in this work.