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Oral Lactoferrin Results in T Cell–Dependent Tumor Inhibition of Head and Neck Squamous Cell Carcinoma In vivo

Authors' Affiliations: ¹ Department of Otorhinolaryngology-Head and Neck Surgery and ² Program in Oncology, Stewart and Marlene Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland; ³ Agennix, Inc., Houston, Texas; and ⁴ Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Jeffrey S. Wolf, Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Suite 500, 16 South Eutaw Street, Baltimore, MD 21201. Phone: 410-328-1887; Fax: 410-328-5827; E-mail: jwolf{at}smail.umaryland.edu.

Purpose: Human lactoferrin is a naturally occurring glycoprotein that inhibits cancer growth. Our purpose was to evaluate recombinant human lactoferrin as a chemotherapeutic agent against head and neck squamous cell carcinoma.

Experimental Design: Controlled experiments both in vitro and in the murine model evaluating both the effect and mechanism of lactoferrin on cancer growth.

Results: In both human and murine cell lines, lactoferrin induced dose-dependent growth inhibition. Using flow cytometric analysis, lactoferrin was shown to induce G₁-G₀ growth arrest. This arrest seemed to be modulated by down-regulation of cyclin D1. In the in vitro model, luminex data revealed that lactoferrin inhibited cellular release of proinflammatory and prometastatic cytokines, including interleukin-8, interleukin-6, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-. Lactoferrin up-regulated the cellular activation of nuclear factor-B within 4 h of cellular exposure. In C3h/HeJ mice implanted with SCCVII tumors, orally delivered lactoferrin inhibited tumor growth by 75% compared with control mice. Immunohistochemical analysis of harvested tumors revealed up to 20-fold increases of lymphocytes within treated animals. When mice were depleted of CD3⁺ cells, all lactoferrin-induced tumor inhibition was abrogated.

Conclusion: We conclude that human recombinant lactoferrin can inhibit the growth of head and neck squamous cell carcinoma via direct cellular inhibition as well as systemically via immunomodulation. Our data support the study of human lactoferrin as an immunomodulatory compound with therapeutic potential.

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