齐留通和塞来昔布对实验性口腔癌抑制作用的研究

Inhibitory effect of Zileuton and Celecoxib on DMBA-induced oral carcinogenesis in hamsters

目的通过局部应用5-Lox抑制剂齐留通和Cox-2抑制剂塞来昔布,研究它们对DMBA诱发的金黄地鼠口腔癌的抑制作用。方法用0.5%的DMBA石蜡油涂于地鼠左侧颊囊,每周3次,共涂6周。从第7周开始分别给地鼠左侧颊囊局部涂抹3%和6%的齐留通、3%和6%的塞来昔布及3%齐留通与3%塞来昔布的混合物,每周3次,连续18周。结果通过局部应用3%和6%的齐留通,鳞状细胞癌的发病率从76.9%分别下降到45·8%(11/24,P<0.05)和32.1%(9/28,P<0.01);应用3%和6%的塞来昔布分别下降到57.6%(15/26,P>0·05)和50.0%(12/24,P<0.05);用3%齐留通与3%塞来昔布的混合物组,鳞状细胞癌的发病率降至36%(9/25,P<0.01)。用药后齐留通组的白三烯B4水平降低;塞来昔布组的前列腺素E2水平降低;联合用药组前列腺素E2和白三烯B4同时降低。结论齐留通和塞来昔布能够抑制DMBA诱发的金黄地鼠口腔癌的发生。齐留通和塞来昔布预防肿瘤的机制可能与其抑制异常花生四稀酸代谢酯氧化酶和环氧合酶途径有关。

Objective To study the inhibitory effect of Zileuton （a specific 5-Lox inhibitor） and Celecoxib （a specific Cox2 inhibitor） on DMBA-induced human oral carcinogenesis. Methods 0.5% DMBA solution in mineral oil was applied topically to the left cheek pouch of male Syrian golden hamsters 3 times per week for 6 weeks. After the last treatment of DMBA, the animals received 3 % and 6% Zileuton, 3 % and 6% Celecoxib, or combination of 3 % Zileuton and 3% Celecoxib applied topically 3 times per week for 18 weeks. Results In a chemoprevention study using the postinitiation DMBA model, incidence of hamster oral squamous cell carcinoma was reduced from 76.9% （20 of 26） to 45.8% （ 11 of 24, P〈0.05） and 32.1% （9 of 28, P〈0.01） by 3% and6% topical Zileuton, respectively;and to 57.6% （15 of 26, P 〉 0. 05） and 50% （ 12 of 24, P 〈 0.05） by 3% and 6% topical Celecoxib, respectively; When used in combination, Celecoxib and Zileuton （3% of each） had an additive inhibitory effect on the incidence of squamous cell carcinoma（36% , 9 of 25, P 〈 0.01 ）. Other pathologic variables and the levels of leukotriene B4 and prostaglandin E2 of the hamster tissues were reduced as well. Conclusion The results suggest that Zileutun and Celecoxib have inhibitory effects against oral carcinogenesis at the post-initiation stage and such inhibition may be related to the suppression of activity of arachidonic acid metabolic enzymes.