In this work, we investigated the anticancer activity of orally administered recombinant human lactoferrin (rhLF) alone and in combination with chemotherapy in tumor-bearing mice. rhLF inhibited the growth of squamous cell carcinoma (O12) tumors in T cell-immunocompromised nu/nu mice by 80% when administered at 1,000 mg/kg (2.9 g/m 2 ) by oral gavage twice daily for 8 days (p < 0.001). Similar activity was observed in syngeneic, immunocompetent BALB/c mice, where orally administered rhLF (1,000 mg/kg, 2.9 g/m 2 once daily) halted the growth of mammary adenocarcinoma TUBO. Oral rhLF (200 mg/kg, 0.57 g/m 2 ) was also used alone and in combination with cis-platinum (5 mg/kg) to treat head-and-neck squamous cell carcinoma in a syngeneic murine model. Monotherapy with oral rhLF or cis-platinum caused 61% or 66% tumor growth inhibition over placebo, respectively. Mice receiving both therapies showed 79% growth inhibition, a statistically significant improvement over each drug alone. We then demonstrated that administration of oral rhLF (300 mg/kg, 0.86 g/m 2 ) to tumor-bearing or naive mice resulted in (i) significantly increased production of IL-18 in the intestinal tract, (ii) systemic NK cell activation and (iii) circulating CD8 ؉ T-cell expansion. These data suggest that oral rhLF is an immunomodulatory agent active against cancer as a single agent and in combination chemotherapy, exerting its systemic effect through stimulation of IL-18 and other cytokines in the gut enterocytes. rhLF has been administered orally to 211 people without a single serious drug-related adverse event. Thus, rhLF shows promise as a safe and well-tolerated novel immunomodulatory anticancer agent.

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 G 1 -G 0 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-a. Lactoferrin up-regulated the cellular activation of nuclear factor-nB 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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SYNOPSISThis work describes the formation of discrete micelles (= 0.1 pm) from ABA poly-(oxyethylene-b-isoprene-b-oxyethylene) block copolymers in water. An efficient labeling of the micelles by polymerization of [ 14C] -styrene within the hydrophobic core is also described. These micellar nanoparticles are being considered as promising materials for controlled release and/or site-specific drug delivery systems. In experimental animals the micelles remained in circulation with a half-life in excess of 50 h. Our results demonstrate the advantages of using block copolymers for the preparation of "perfect" biocompatible surfaces such as are required for well-tolerated, long-circulating particulate drug carriers.

Objective To evaluate safety and explore efficacy of recombinant human lactoferrin (talactoferrin, TLf) to reduce infection. Study design We conducted a randomized, double blind, placebo-controlled trial in 6 0 infants with birth weights of 750 to 1500 grams. Each infant received enteral TLf or placebo on day 1 through 28 days of life; TLf dose was 150 mg/kg/12 hour. Primary outcomes were bacteremia, pneumonia, urinary tract infection, meningitis and necrotizing enterocolitis. Secondary outcomes were sepsis syndrome and suspected NEC. We recorded clinical, laboratory and radiologic findings, diseases, and adverse events in a database used for statistical analyses. Results Infants in the two groups had similar demographics. We attributed no enteral or organ-specific adverse events to TLf. There were two deaths in the group with TLf (posterior fossa hemorrhage and post-discharge sudden infant death), and one infant given placebo died of necrotizing enterocolitis. Hospital-acquired infections in the group with Tlf were 50% of that observed in infants fed placebo (p<0.04), including fewer blood or line infections, urinary tract infections, and pneumonia. Fourteen infants treated with TLf-weighing <1 kg at birth weight had no Gram-negative infections versus three of 14 infants given placebo. Non-infectious outcomes did not differ statistically in the two arms. No differences in growth or neurodevelopment occurred among infants treated with TLf and placebo during a one-year, post-hospitalization period. Conclusion We found no clinical or laboratory toxicity and a trend towards less infectious morbidity in infants treated with TLf. Trial registration ClinicalTrials.gov: NCT00854633.