title: Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy.
abstract: 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/m2) 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/m2 once daily) halted the growth of mammary adenocarcinoma TUBO. Oral rhLF (200 mg/kg, 0.57 g/m2) 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/m2) 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.
authors.affiliation: Agennix, Inc., Houston, TX 77046, USA. avaradhachary@agennix.com
authors.forename: Atul
authors.initials: A
authors.lastname: Varadhachary
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wolf
authors.forename: Karel
authors.initials: K
authors.lastname: Petrak
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Michela
authors.initials: M
authors.lastname: Spadaro
authors.forename: Claudia
authors.initials: C
authors.lastname: Curcio
authors.forename: Guido
authors.initials: G
authors.lastname: Forni
authors.forename: Federica
authors.initials: F
authors.lastname: Pericle
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007781:Lactoferrin / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D007781:Lactoferrin; D002945:Cisplatin