Experimental study on therapy for oral cancer by cyclooxygenase-2 inhibitors

我们分析了选择性环氧合酶(COX)-2抑制剂尼美舒利和依托度酸在4-硝基喹啉1-氧化物(4-NQO)诱导的大鼠舌癌变模型中的作用，以评价它们对口腔癌的化学预防作用，并报道了这些抑制剂对鳞状细胞癌(SCCs)和鳞状细胞增生性病变、癌前病变的抑制作用。本研究旨在探讨环氧合酶-2在大鼠舌癌变过程中的作用。大鼠给予4-NQO(25-35ppm)12周，然后给予依托度酸(150ppm和300ppm)16周。分析依托度酸对肿瘤及癌前病变发生率的影响，以及COX-2和诱导型一氧化氮合酶(INOS)在这些病变中的免疫组织化学表达。300ppm的依托度酸可显著抑制鳞状细胞癌的发生，使其发生率从100%增加到50%，同时伴随着异型增生发生率的增加。鳞状细胞的大小也减小。这些结果表明依托度酸抑制了异型增生向鳞状细胞的发展，并抑制了鳞状细胞的增殖能力。环氧合酶-2和诱导型一氧化氮合酶的免疫组织化学研究显示依托度酸对环氧合酶-2和诱导型一氧化氮合酶的表达没有影响。由此可见，依托度酸对SCCs的抑制作用不是通过抑制COX-2蛋白的表达，而是通过抑制COX-2的酶活性来实现的。

We analyzed the efficacy of selective cyclooxygense(COX)-2 inhibitors, nimesulide and etodolac, in the rat model of tongue carcinogenesis using 4-nitroquinoline 1-oxide(4-NQO) in order to evaluate their chemopreventive efficacy on human oral cancers and reported the suppressive effect of these inhibitors on the development of squamous cell carcinomas(SCCs) and squamous cell daplasias, putative preneoplastis lesions. The present study was conducted to elucidate the roles of COX-2 in rat tongue carcinogenesis. Rats were administered 4-NQO (25-35 ppm) for 12 weeks and then etodolac (150ppm and 300ppm) was given for 16 weeks. The effect of etodolac on the incidence of neoplastic and preneoplastic lesions and the immunohistochemical expression of COX-2 and inducible nitoric oxide synthase (iNOS) in these lesions were analyzed. Etodolac at the dose of 300ppm significantly suppressed the incidence of SCCs from 100% to 50% in parallel with the increase of the incidence of dysplasias. The size of SCCs was also decreased. These results indicate that etodolac suppressed the progression of dysplasias to SCCs and the proliferative potential of SCCs. Immunohistochemical study on the expression of COX-2 and iNOS revealed that etodolac had no effect on the expression of COX-2 or iNOS. From these results, it is considered that the suppressive effect of etodolac on the development of SCCs was not exerted by the inhibition of COX-2 protein expression but by the inhibition of the enzymatic activity of COX-2.