Robertson F M, Ross M S, Tober K L, Long B W, Oberyszyn T M
Ohio State University Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus 43210, USA.
Carcinogenesis. 1996 Aug;17(8):1719-28. doi: 10.1093/carcin/17.8.1719.
Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of Sencar mice induces synthesis of pro-inflammatory cytokines, including interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha). 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-oxohexyl)-3,7-dimethyl-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 10 micrograms 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 micrograms/g pentoxifylline at 30 min prior to topical application of 10 micrograms TPA to the dorsal epidermis of Sencar mice inhibited TPA-induced IL-1 alpha and TNF-alpha 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). Injection of 50 micrograms/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 effective means of inhibiting acute TPA-induced cutaneous inflammation and pro-inflammatory cytokine gene expression, as well as is effective as an antipromoter that inhibits papilloma growth.
将12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）局部应用于Sencar小鼠的背部表皮，可诱导促炎细胞因子的合成，包括白细胞介素 - 1α（IL - 1α）和肿瘤坏死因子 - α（TNF - α）。这些蛋白质对表皮角质形成细胞的增殖有不同的调节作用，还能刺激白细胞的趋化性、迁移以及活性氧和氮中间体的产生。过去几年的研究表明，己酮可可碱（[1 - (5 - 氧代己基)-3,7 - 二甲基 - 黄嘌呤]，氧甲吡嗪），一种临床上用于治疗血管功能不全的甲基黄嘌呤衍生物，具有抑制促炎细胞因子合成的独特能力。本研究旨在检查急性和慢性给予己酮可可碱对单次用10微克TPA处理的雌性Sencar小鼠TPA诱导的皮肤炎症的影响，并确定己酮可可碱抑制单次应用25纳摩尔7,12 - 二甲基苯并[a]蒽（DMBA）后每周两次局部应用TPA处理8周的小鼠肿瘤促进过程的能力。在向Sencar小鼠背部表皮局部应用10微克TPA前30分钟腹腔注射50微克/克己酮可可碱，可抑制TPA处理24小时后TPA诱导的IL - 1α和TNF - α基因表达。给予己酮可可碱还显著抑制了24小时后检测的急性TPA诱导的炎症反应的所有参数，包括皮肤增厚（P < 0.005）、中性粒细胞浸润到真皮（P < 0.001）、相应的真皮髓过氧化物酶活性（P < 0.01）和表皮增生（P < 0.001）。在8周时间内注射50微克/克己酮可可碱显著抑制了DMBA/TPA诱导的乳头状瘤生长（P < 0.05）。这些结果表明，给予己酮可可碱是抑制急性TPA诱导的皮肤炎症和促炎细胞因子基因表达的有效手段，并且作为一种抑制乳头状瘤生长的抗促癌剂也是有效的。
