Journal Article

Inhibitation of pro-inflammatory cytokine gene expression and papilloma growth during murine multistage carcinogenesis by pentoxifylline

Fredika M. Robertson, Mary S. Ross, Kathleen L. Tober, Brooks W. Long and Tatiana M. Oberyszyn

in Carcinogenesis

Volume 17, issue 8, pages 1719-1728
Published in print August 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.8.1719
Inhibitation of pro-inflammatory cytokine gene expression and papilloma growth during murine multistage carcinogenesis by pentoxifylline

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Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of Sencar mice induces synthesis of pro-inflammatory cytokines, including interleukin-1α (IL-1αa) and tumor necrosis factor-α (TNF-α). These proteins differentially regulate proliferation of epidermal keratinocytes, as well as stimulate chemotaxis, migration and production of reactive oxygen and nitrogen intermediates by leukocytes. Studies over the past several years have demonstrated that pentoxifylline ([1-(5-oxo-hexyl)-3, 7-dimenthyl-xanthine], oxpentifylline), which is a methylxanthine derivative used clinically for treatment of vascular insufficiency, has the unique ability to inhibit synthesis of pro-inflammatory cytokines. The present studies were performed to examine the effects of acute and chronic administration of pentoxifylline on TPA-induced cutaneous inflammation in female Sencar mice treated once with 10μg TPA and also to determine the ability of pentoxifylline to inhibit the tumor promotion process in mice treated with a single application of 25 nmol 7, 12-dimethylbenz[a]anthracene (DMBA) followed for 8 weeks by twice weekly topical application of TPA. Intraperitoneal injection of 50 μg/g pentoxifylline at 30 min prior to topical application of 10 μg TPA to the dorsal epidermis of Sencar mice inhibited TPA-induced IL-1α and TNF-α gene expression 24 h after TPA treatment. Administration of pentoxifylline also significantly inhibited all parameters of acute TPA-induced inflammatory response examined 24 h later, including skin thickening (P<0.005), infiltration of neutrophils into the dermis (P < 0.001), the corresponding dermal myeloperoxidase activity (P<0.01) and epidermal hyperplasia (P<0.001). Injuction of 50 μg/g pentoxifylline over an 8 week time period significantly inhibited DMBA/TPA-induced papilloma growth (P<0.05). These results indicate that administration of pentoxifylline is an effectivemeans of inhibiting acute TPA-induced cutaneous inflammation and pro-inflammatory cytokine gene expression, as well as is effective as an anti-promoter that inhibits papilloma growth.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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