Clinical Studies on Lactoferrin

(There are clinical studies topically related to our research here. We prefer to base our nutritional products on clinical studies more than testimonies. Some studies are listed at the end of particular articles. More can be found under the general topics of Monolaurin, Lactoferrin, Essential Oils, etc.)

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It is known that lactoferrin inhibits cell proliferation and suppresses tumor growth. It arrests the growth of these cells at the G1 [growth and preparation of the chromosomes for replication] to S [DNA synthesis] transition of the cell cycle. Therefore, lactoferrin induces growth arrest by modulating the expression and activity of key G1 regulatory proteins.

Damiens E, EI Yazidi I, Mazurier J, Duthille I, Spik G, Boilly-Marer Y. Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells. Journal of Cell Biochemistry, 74(3):486–498 (1999).

Human lactoferrin applied at levels found in inflammation was found to boost the cytotoxic activity of natural killer (NK) cells against hematopoietic and breast epithelial tumor cell lines. It also significantly increases the susceptibility to lysis of breast and colon epithelial tumor cell lines…shown to inhibit epithelial cell proliferation by blocking cell cycle progression.

Damiens E, Mazurier J, EI Yazidi I, Masson M, Duthille I, Spik G, Boilly-Marer Y. Effects of human lactoferrin on NK cell cytotoxicity against hematopoietic and epithelial tumor cells. Biochimica et Biophysica Acta, 1402(3):277–287 (1998).

Oral administration of bovine lactoferrin …the effects on metastasis of colon carcinoma to the lung was studied and significant inhibition of metastasis was found. The results suggest that the anti-metastatic effect of lactoferrin may be due to enhanced cellular immunity.

Kuhara T, Ligo M, Itoh T, Ushida Y, Sekine K, Terada N, Okamura H, Tsuda H. Orally administered lactoferrin exerts an anti-metastatic effect and enhances production of Il-18 in the intestinal epithelium. Nutrition and Cancer, 38(2):192–199 (2000).

Inhibition of azoxymethane-initiated colon tumor by bovine lactoferrin administration in F344 rats. Japanese Journal of Cancer Research 88(6):523–526 (1997). Rats that received a stronger dose of lactoferrin, 2%, had only a 15% (vs 57.5%) rate of tumor development.

Sekine K, Watanabe E, Nakamura J, Takasuka N, Kim DJ, Asamoto M, Krutovskikh Y, Baba-Toriyama H, Ota T, Moore MA, Masuda M, Sugimoto H, Nishino H, Kakizoe T, Tsuda H.

Review article of studies which indicate that bovine lactoferrin is an effective anticancer agent in rat studies; capable of significantly inhibiting colon, esophagus, lung, bladder, and tongue carcinogenesis. It was also found that lactoferrin has significant anti-Hepatitis C virus activity; Hepatitis C is a leading cause of liver cancer in Japan.

Tsuda H, Sekine K, Fujita K, Ligo M. Cancer prevention by bovine lactoferrin and underlying mechanisms—A review of experimental and clinical studies. Biochemistry and Cell Biology, 80(1):131–136 (2002).

It was found again that a 2% lactoferrin solution produced better protection against the development of carcinoma than the weaker 0.2% solution, though both provided more protection than the control group. With a 2% solution, only 20% of the rats developed cancer, and they showed 64% less multiple tumors than the control group.

Tanaka T, Kawabata K, Kohno H, Honjo S, Murakami M, Ota T, Tsuda H. Chemopreventive effect of bovine lactoferrin on 4-nitroquinoline I-oxide-¬induced tongue carcinogenesis in male F344 rats. Japanese Journal of Cancer Research, 91(1):25–33 (2000).

(Additional Clinical Studies)

Agostina Pietrantoni, Assunta Maria Di Biase, Antonella Tinari, Magda Marchetti, Piera Valenti, Lucilla Seganti, and Fabiana Superti, Bovine Lactoferrin Inhibits Adenovirus Infection by Interacting with Viral Structural Polypeptides, Department of Ultrastructure, Istituto Superiore di Sanità, Department of Experimental Medicine, II University of Naples, Naples, Italy, Accepted 8 May 2003

Arnold D, Di Biase AM, Marchetti M, Pietrantoni A, Valenti P, Seganti L, Superti F (2002). “Antiadenovirus activity of milk proteins: lactoferrin prevents viral infection”. Antiviral Res. 53 (2): 153–8. doi:10.1016/S0166-3542(01)00197-8. PMID 11750941.

Bhimani RS, Vendrov Y, Furmanski P. Influence of lactoferrin feeding and injection against systemic staphylococcal infections in mice. J Appl Microbiol 1999 Jan;86(1):135-44.

Defer MC, Dugas B, Picard O, Damais C. Impairment of circulating lactoferrin in HIV-1 infection. Cell Mol Biol (Noisy-le-grand) 1995 May;41(3):417-21.

Dial EJ, Hall LR, Serna H, Romero JJ, Fox JG, Lichtenberger LM. Antibiotic properties of bovine lactoferrin on Helicobacter pylori. Dig Dis Sci 1998 Dec;43(12):2750-6.

Farnaud S, Evans RW (2003). “Lactoferrin–a multifunctional protein with antimicrobial properties”. Mol. Immunol. 40 (7): 395–405.

Giansanti F, Rossi P, Massucci MT, Botti D, Antonini G, Valenti P, Seganti L (2002). “Antiviral activity of ovotransferrin discloses an evolutionary strategy for the defensive activities of lactoferrin”. Biochem. Cell Biol. 80 (1): 125–30. doi:10.1139/o01-208. PMID 11908636.

Harmsen MC, Swart PJ, de Béthune MP, Pauwels R, De Clercq E, The TH, Meijer DK (1995). “Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro”. J. Infect. Dis. 172 (2): 380–8. PMID 7622881.

Inglot AD, Janusz M, Lisowski J. Colostrinine, a Proline-rich Polypeptide from ovine colostrum, is a modest cytokine inducer in human leukocytes. Archivum immunologiae et therapiae experimentalis (Warszava), 44(4):215–224 (1996).

Jing-Fen Kang, Xiang-Long Li, Rong-Yan Zhou, Lan-Hui Li, Fu-Jun Feng and Xiu -Li Guo (2008). “Bioinformatics Analysis of Lactoferrin Gene for Several Species”. Biochemical Genetics 46 (5-6): 312–322. doi:10.1007/s10528-008-9147-9. PMID 18228129.

Kruzel ML, Harari Y, Chen CY, Castro GA. The gut. A key metabolic organ protected by lactoferrin during experimental systemic inflammation in mice. Adv Exp Med Biol 1998;443:167-73.

Kuipers ME, de Vries HG, Eikelboom MC, Meijer DK, Swart PJ (1999). “Synergistic fungistatic effects of lactoferrin in combination with antifungal drugs against clinical Candida isolates”. Antimicrob. Agents Chemother. 43 (11): 2635–41. PMID 10543740.

Kuwata H, Yip TT, Tomita M, Hutchens TW. Direct evidence of the generation in human stomach of an antimicrobial peptide domain (lactoferricin) from ingested lactoferrin. Biochim Biophys Acta 1998 Dec 8;1429(1):129-41.

Kuwata H, Yip TT, Yip CL, Tomita M, Hutchens TW (1998). “Bactericidal domain of lactoferrin: detection, quantitation, and characterization of lactoferricin in serum by SELDI affinity mass spectrometry”. Biochem. Biophys. Res. Commun. 245 (3): 764–73.

Levay PF, Viljoen M (1995). “Lactoferrin: a general review”. Haematologica 80 (3): 252–67.

Lidbeck A, Allinger UG, Orrhage KM, Ottova L, Brismar B, Gustafsson JA, Rafter J, Nord CE. Impact of Lactobacillus Acidophilus Supplements on the Fecal Microflora and Soluble Fecal Bile Acids in Colon Cancer Patients. Microbial Ecology in Health and Disease, 4:81–88 (1991).

Lupetti A, Paulusma-Annema A, Welling MM, Dogterom-Ballering H, Brouwer CP, Senesi S, Van Dissel JT, Nibbering PH (2003). “Synergistic activity of the N-terminal peptide of human lactoferrin and fluconazole against Candida species”. Antimicrob. Agents Chemother. 47 (1): 262–7. doi:10.1128/AAC.47.1.262-267.2003. PMID 12499200.

Masci, JR (2000). “Complete response of severe, refractory oral candidiasis to mouthwash containing lactoferrin and lysozyme.”. AIDS (London, England) 14 (15): 2403–4. PMID 11089630.

Mazurier J, Spik G (1980). “Comparative study of the iron-binding properties of human transferrins. I. Complete and sequential iron saturation and desaturation of the lactotransferrin”. Biochim. Biophys. Acta 629 (2): 399–408.

Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B (2007). “A novel host defense system of airways is defective in cystic fibrosis”. Am. J. Respir. Crit. Care Med. 175 (2): 174–83. doi:10.1164/rccm.200607-1029OC. PMID 17082494.

Naidu AS (2000). Lactoferrin: natural, multifunctional, antimicrobial. Boca Raton: CRC Press. pp. 1–2. ISBN 0-8493-0909-3.

Nozaki A, Ikeda M, Naganuma A, Nakamura T, Inudoh M, Tanaka K, Kato N (2003). “Identification of a lactoferrin-derived peptide possessing binding activity to hepatitis C virus E2 envelope protein”. J. Biol. Chem. 278 (12): 10162–73. doi:10.1074/jbc.M207879200. PMID 12522210.

Olszewska Z, Janusz M. Stimulatory effect of ovine colostrinine (a Proline-¬rich Polypeptide) on interferons and tumor necrosis factor production by murine resident peritoneal cells. Archivum immunologiae et therapiae experimentalis (Warszava), 45(1):43–47 (1997).

“Public summary of positive opinion for orphan designation of hypothiocyanite/lactoferrin for the treatment of cystic fibrosis”. Pre-authorisation Evaluation of Medicines for Human Use. European Medicines Agency. 2009-09-07. Retrieved 2010-01-23.

Puddu P, Borghi P, Gessani S, Valenti P, Belardelli F, Seganti L (1998). “Antiviral effect of bovine lactoferrin saturated with metal ions on early steps of human immunodeficiency virus type 1 infection”. Int. J. Biochem. Cell Biol. 30 (9): 1055–62. doi:10.1016/S1357-2725(98)00066-1. PMID 9785469.

Rosenmund A, Kuyas C, Haeberli A (1986). “Oxidative radioiodination damage to human lactoferrin”. Biochem. J. 240 (1): 239–45. PMID 3827843.

Sakamoto N. Antitumor effect of human lactoferrin against newly established human pancreatic cancer cell line SPA. Gan To Kagaku Ryoho 1998 Aug;25(10):1557-63.

Shongwe MS, Smith CA, Ainscough EW, Baker HM, Brodie AM, Baker EN (1992). “Anion binding by human lactoferrin: results from crystallographic and physicochemical studies”. Biochemistry 31 (18): 4451–8.

Swart PJ, Kuipers EM, Smit C, Van Der Strate BW, Harmsen MC, Meijer DK. Lactoferrin. Antiviral activity of lactoferrin. Adv Exp Med Biol 1998;443:205-13.

Tsuda H, Sekine K, Nakamura J, Ushida Y, Kuhara T, Takasuka N, Kim DJ, Asamoto M, Baba-Toriyama H, Moore MA, Nishino H,

Kakizoe T. Inhibition of azoxymethane initiated colon tumor and aberrant crypt foci development by bovine lactoferrin administration in F344 rats. Adv Exp Med Biol 1998;443:273-84.

Ushida Y, Sekine K, Kuhara T, Takasuka N, Iigo M, Tsuda H. Inhibitory effects of bovine lactoferrin on intestinal polyposis in the Apc(Min) mouse. Cancer Lett 1998 Dec 25;134(2):141-5.

van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK (2001). “Antiviral activities of lactoferrin”. Antiviral Res. 52 (3): 225–39.

Viejo-Díaz M, Andrés MT, Fierro JF (2004). “Modulation of in vitro fungicidal activity of human lactoferrin against Candida albicans by extracellular cation concentration and target cell metabolic activity”. Antimicrob. Agents Chemother. 48 (4): 1242–8. doi:10.1128/AAC.48.4.1242-1248.2004. PMID 15047526.

Vorland LH, Ulvatne H, Andersen J, Haukland H, Rekdal O, Svendsen JS, Gutteberg TJ. Lactoferricin of bovine origin is more active than lactoferricins of human, murine and caprine origin. Scand J Infect Dis 1998;30(5):513-7.

Yamauchi K, Wakabayashi H, Hashimoto S, Teraguchi S, Hayasawa H, Tomita M. Effects of orally administered bovine lactoferrin on the immune system of healthy volunteers. Adv Exp Med Biol 1998;443:261-5.

Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I. Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Jpn J Cancer Res 1997 Feb;88(2):184-90.

Zhang GH, Mann DM, Tsai CM. Neutralization of endotoxin in vitro and in vivo by a human lactoferrin-derived peptide. Infect Immun 1999 Mar;67(3):1353-8.

Zimecki M, Wlaszczyk A, Cheneau P, Brunel AS, Mazurier J, Spik G, Kubler A. Immunoregulatory effects of a nutritional preparation containing bovine lactoferrin taken orally by healthy individuals. Arch Immunol Ther Exp (Warsz) 1998;46(4):231-40.