Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma
Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma
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DOI：
10.1093/carcin/bgs349
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发表时间：
2013-02-01
期刊：
影响因子：
4.7
通讯作者：
Oberyszyn, Tatiana M.
中科院分区：
文献类型：
--
作者：
Burns, Erin M.;Tober, Kathleen L.;Oberyszyn, Tatiana M.
中波紫外线（UVB）是导致非黑素瘤皮肤癌（NMSC）发生的主要环境致癌物。每年有200万患者被诊断出患有超过350万例NMSC，男性患鳞状细胞癌（SCC）的发病率是女性的3倍。慢性炎症与肿瘤发生有关，其中环氧化酶 - 2（COX - 2）酶起着关键作用。双氯芬酸是一种COX - 2抑制剂和非甾体抗炎药，目前作为一种短期治疗药物开给患者，用于诱导SCC前体病变消退。然而，对于没有前体病变迹象但有明显UVB诱导的皮肤损伤的患者，其作为预防药物的功效尚未得到研究。我们之前在一个UVB诱导的皮肤癌发生的小鼠模型中证明，当暴露于等量的UVB剂量时，与雌性小鼠相比，雄性小鼠炎症水平较低，但肿瘤的多发性、负荷和分级却增加。由于雄性和雌性皮肤炎症程度的差异，我们试图确定用抗炎的COX - 2抑制剂对先前受损的皮肤进行局部治疗是否会降低肿瘤负荷，以及在两性中是否同样有效。我们的结果表明，尽管在炎症反应中观察到性别差异，但对长期受UVB损伤的皮肤进行长时间的局部双氯芬酸治疗，有效地降低了两性的肿瘤多发性。出乎意料的是，肿瘤负荷仅在雄性小鼠中显著降低。我们的数据表明，现有的局部用双氯芬酸有一种新的治疗用途，可作为在病变出现之前易患皮肤SCC的患者的一种预防性干预措施。
Ultraviolet B (UVB) light is the major environmental carcinogen contributing to non-melanoma skin cancer (NMSC) development. There are over 3.5 million NMSC diagnoses in two million patients annually, with men having a 3-fold greater incidence of squamous cell carcinoma (SCC) compared with women. Chronic inflammation has been linked to tumorigenesis, with a key role for the cyclooxygenase-2 (COX-2) enzyme. Diclofenac, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, currently is prescribed to patients as a short-term therapeutic agent to induce SCC precursor lesion regression. However, its efficacy as a preventative agent in patients without evidence of precursor lesions but with significant UVB-induced cutaneous damage has not been explored. We previously demonstrated in a murine model of UVB-induced skin carcinogenesis that when exposed to equivalent UVB doses, male mice had lower levels of inflammation but developed increased tumor multiplicity, burden and grade compared with female mice. Because of the discrepancy in the degree of inflammation between male and female skin, we sought to determine if topical treatment of previously damaged skin with an anti-inflammatory COX-2 inhibitor would decrease tumor burden and if it would be equally effective in the sexes. Our results demonstrated that despite observed sex differences in the inflammatory response, prolonged topical diclofenac treatment of chronically UVB-damaged skin effectively reduced tumor multiplicity in both sexes. Unexpectedly, tumor burden was significantly decreased only in male mice. Our data suggest a new therapeutic use for currently available topical diclofenac as a preventative intervention for patients predisposed to cutaneous SCC development before lesions appear.