Abstract
We examined the effects of roxithromycin, a 14-membered ring macrolide antibiotic, on tumor angiogenesis, tumor growth and metastasis of mouse B16BL6 melanoma cells. The inhibitory effect of roxithromycin on angiogenesis using mouse dorsal air sac model was dose-dependent, and 100 mg/kg of roxithromycin administered intraperitoneally twice a day reduced the dense capillary network area to about 20% of the control. Administration of roxithromycin histologically reduced the development of microvessels and mononuclear cell infiltration. In vivo tumor growth studies demonstrated that intraperitoneal administration of roxithromycin at 20 mg/kg/day and 50 mg/kg/day reduced tumor size of B16BL6 melanoma to about 56% and 33% (experiment 1), 71% and 48% (experiment 2) of that in the respective controls. Roxithromycin also significantly inhibited pulmonary metastasis of B16BL6 cells in a spontaneous system. The inhibitory activities of roxithromycin on angiogenesis, tumor growth and metastasis were compared with those of a potent angiogenesis inhibitor, TNP-470. These data demonstrated that roxithromycin has potent antiangiogenic and antitumor effects and might have possible therapeutic applications.
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References
Folkman J. Tumor angiogenesis. In: Mendelsohn J, Howley PM, Israel MA, Liotta LA (eds) The Molecular Basis of Cancer. Philadelphia: W. B. Saunders 1995; 206–32.
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1955; 1: 27–31.
Folkman J. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333: 1757–63.
O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA et al. Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315–28.
O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G et al. Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–85.
Karp JE, Broder S. Molecular foundations of cancer: new targets for intervention. Nat Med 1995; 1: 309–20.
Agen C, Danesi R, Blandizzi C et al. Macrolide antibiotics as antiinflammatory agents: roxithromycin in an unexpected role. Agents Actions 1993; 38: 85–90.
Kadota J, Saito O, Kohno S et al. A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. Am Rev Respir Dis 1993; 147: 153–9.
Oishi K, Sonoda F, Kobayashi S et al. Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients with chronic airway diseases. Infect Immun 1994; 62: 4145–52.
Takizawa H, Desaki M, Ohtoshi T et al. Erythromycin suppresses interleukin-6 expression by human epithelial cells: a potential mechanism of its anti-inflammatory action. Biochem Biophys Res Commun 1995; 210: 781–6.
Mitsuyama T, Hidaka K, Furuno T et al. Neutrophil-induced endothelial cell damage: inhibition by a 14–membered ring macrolide through the action of nitric oxide. Int Arch Allergy Immunol 1997; 114: 111–5.
Yatsunami J, Tsuruta N, Wakamatsu K et al. Clarithromycin is a potent inhibitor of tumor induced angiogenesis. Res Exp Med (Berlin) 1997; 197: 189–97.
Yatsunami J, Tsuruta N, Hara N et al. Inhibition of tumor-induced angiogenesis by roxithromycin, a 14–membered ring macrolide antibiotic. Cancer Lett 1998 (in press).
Taniguchi S, Fujiki H, Kobayashi H et al. Effect of (_)-epigallocatechin gallate, the main constituent of green tea, on lung metastasis with mouse B16 melanoma cell lines. Cancer Lett 1992; 65: 51–4.
Yatsunami J, Tsuruta N, Ogata K et al. Interleukin-8 participates in angiogenesis in non-small cell, but not small cell carcinoma of the lung. Cancer Lett 1997; 120: 101–8.
Antoine N, Greimers R, Roanne MD et al. AGM-1470, a potent angiogenesis inhibitor, prevents the entry of normal but not transformed endothelial cells into the G1 phase of the cell cycle. Cancer Res 1994; 54: 2073–6.
Ingber D, Fujita T, Kishimoto S et al. Synthetic analogs of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 1998; 348: 555–7.
Yamaoka M, Yamamoto T, Masaki T et al. Inhibition of tumor growth and metastasis of rodent tumors by the angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470; AGM-1470). Cancer Res 1993; 53: 4262–7.
Castronovo V, Belloti D. TNP-470 (AGM-1470): mechanisms of action and early clinical development. Eur J Cancer 1996; 32: 2520–7.
Sin N, Meng L, Wang MQW et al. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci 1997; 94: 6099–103.
Konno S, Adachi M, Asano K et al. Influence of roxithromycin on cell-mediated immune responses. Life Sci 1992; 51: 107–12.
Yoshimura T, Kurita C, Yamazaki F et al. Effects of roxithromycin on proliferation of peripheral blood mononuclear cells and production of lipopolysaccharide-induced cytokines. Biol Pharm Bull 1995; 18: 876–81.
Hamada K, Kita E, Sawaki M et al. Antitumor effect of erythromycin in mice. Chemotherapy 1995; 41: 59–69.
Mikasa K, Sawaki M, Kita E et al. Significant survival benefit to patients with advanced non-small lung cancer from treatment with clarithromycin. Chemotherapy 1997; 43: 288–96.
Twardowski P, Gradishar WJ. Clinical trials of antiangiogenic agents. Curr Opin Oncol 1997; 9: 584–89.
Kusano S, Kadota J, Kohno S et al. Effects of roxithromycin on peripheral neutophil adhesion molecules in patients with chronic lower respiratory tract disease. Respiration 1995; 62(4): 217–22.
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Yatsunami, J., Tsuruta, N., Fukuno, Y. et al. Inhibitory effects of roxithromycin on tumor angiogenesis, growth and metastasis of mouse B16 melanoma cells. Clin Exp Metastasis 17, 119–124 (1999). https://doi.org/10.1023/A:1006591805332
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DOI: https://doi.org/10.1023/A:1006591805332