以環氧化酵素二型(COX-2)抑制劑做為口腔癌前病變之化學預防

Abstract

根據中華民國行政院衛生署國民健康局所發布九十六年癌症登記報告指出，口腔癌目前已成為台灣男性十大癌症中新增率最高的癌症，平均死亡年齡五十四歲，堪稱男性青壯年殺手。口腔癌的治療常造成巨大的顏面外觀損害及飲食機能改變，五年存活率整體也僅有五成五左右，末期(第四期)病患存活率更是減至四成以下。口腔癌常常會發生第二原發性腫瘤，因此，雖然目前的手術方式、放射線及化學治療都較從前有長足的進步，其生存率仍沒有重大起色。因此能夠在癌症早期甚至是尚未產生癌症時就予以預防及抑制產生，是一個相當值得研究的課題。 化學預防(chemoprevention)的概念是在一九七六年由Sporn所提出，利用一些自然或是合成的特定製劑對於侵襲性癌症有回復、抑制或是防止惡化的效果。已有許多研究證實非類固醇抗發炎類藥物(non-steroidal anti-inflammatory drugs, NSAIDs)可以透過抑制環氧化酵素二型(cyclooxygenase-2, COX-2)來預防大腸直腸癌。考慮到大腸直腸癌的成因與口腔癌有許多相似之處，因此我們也對於NASIDs類藥物是否也可以在口腔組織有相同的功效特別有興趣。 我們遵循既有的診斷模式，先以病變處組織切片的病理診斷，初步篩選出有口腔癌前病變之受試者，再經由所訂定的受試者納入條件，選出符合條件的最後受試者。服用三個月的希樂葆(CELEBREX®)後，觀察其癌前病灶之變化，並再次於病灶處進行切片手術。然後就其臨床診斷、化學預防前後組織切片之病理診斷、免疫組織化學染色結果及病患本身之嚼食檳榔、抽菸及飲酒習慣等資料做比較，期待能找出以COX-2選擇性抑制劑做為化學預防的效果及角色。 結果發現，三個月的化學預防後，病灶處無明顯之改變，病理診斷也無顯著差異。不過可以發現，組織中COX-2表現明顯地下降，而且與細胞增殖有關的Ki-67之表現有正相關性，但與細胞凋亡相關的Bcl-2與Survivin無關聯性。我們也發現，抽菸、喝酒及嚼食檳榔等習慣都對於COX-2抑制劑的抑制效果都有所影響。三個月的化學預防期間，受試者皆沒有出現任何心血管方面的副作用，也沒有嚴重的身體不適情況。受試者在經過第二次切片手術後，繼續接受常規的治療，追蹤觀察至今，有超過半數以上的受試者已達到完全反應(complete response, CR)，並且無復發的跡象。 三個月的化學預防療程，對於原先病灶處的減小及消除是無效的，但在組織中的確可以發現COX-2表現減少的情況，因此原病灶後續的進展以及日後他處是否有癌前病變出現的情況，仍具有相當的研究價值。COX-2被抑制後，對於細胞增殖的路徑有所影響，但是對於細胞凋亡路徑的影響性還需要再確認。另外，不良口腔習慣的確會對於COX-2的抑制效果產生影響，因此，當大部分受試者仍持續有這些習慣時，對於短期內化學預防效果的研判是有影響的。我們認為COX-2化學預防應有其價值功效，但仍須有更大規模、更多控制變因且更嚴謹的研究設計來探討其角色與價值。

In Taiwan, especially due to the habit of betel quid chewing, the annual incidence of oral cancer is more than 4,000 cases. This disease combines with severe morbidity, which results in the 5-year survival rate is about 55% only. Oral cancer is frequently preceded by multifocal oral potentially malignant disorders (PMD) during multistep carcinogenesis, but there is still no better approach proved to be able to attenuate the occurring of oral cancer by the turnover of oral PMD. Cyclooxygenase-2 (COX-2) is induced by many factors including inflammatory stimuli, growth factors, tumor promoters, oncogenes, and carcinogens. Overexpression of COX-2, therefore, will inhibit many reactions like apoptosis, and increase cell proliferation, promote angiogenesis, or suppress immune surveillance, thus encourages the accumulation of genetic damage in epithelial cells. Previous in vitro and in vivo studies showed that COX-2 is overexpressed in oral PMD and head and neck squamous cell carcinoma, those results led us to hypothesize that inhibiting COX-2 in premalignant tissue would be an effective chemopreventive strategy for patients with oral PMD. In order to investigate the hypothesis, we go on this study. In our study, 26 participants were recruited to give celecoxib, 400mg twice daily, for 12weeks. Biopsies were applied at baseline day and week 12. All participants enrolled in the study were required to have at least one pathologically proved oral PMD (hyperkeratosis, mild dysplasia and moderate dysplasia). After that, we evaluated the efficacy, safety and influences of celecoxib in patients with oral PMD. We also compared the effect of oral habits (betel quid chewing, cigarette smoking and alcohol drinking) with the efficacy of chemoprevention. After 12-week chemoprevention, there were no significant differences in many characters including the size, the thickness, the color and the texture of the lesions, and there were also no obvious changes in pathological diagnosis. But we found COX-2 expression was significantly decreased and Ki-67 expression was positively correlated with COX-2 expression, however, there was no correlation in the expression of Survivin and Bcl-2 compared with COX-2. We also found that cigarette smoking, alcohol drinking and betel quid chewing were impacts for inhibition of COX-2 expression. In the periods of this study, participants had no cardiovascular side effects or serious illness situation. After the second biopsy, participants whose lesions still existed continued to have further treatments (cryotherapy, photodynamic therapy or surgical excision) and to be follow up so far（about 2 years）, more than half of those participants’ diseases were completely healed without recurrence. Three-month chemoprevention regimen for the remission or reduction of the oral precancerous lesion was ineffective. However, keeping follow-up the original lesion still had the considerable research value. COX-2 might affect cell proliferation, but the impact of the pathway of apoptosis by taking celecoxib still need to be confirmed. In addition, bad oral habits will indeed affect COX-2 inhibition and therefore, while most of the participants continued to have those habits, we couldn’t easily judge the efficacy of COX-2 chemoprevention. Our results showed that COX-2 chemoprevention should possess its own value, but it is necessary to have more rigorous studies to investigate the role and value of COX-2 chemoprevention.