組織蛋白去乙醯酶抑制劑和5-氟尿嘧啶聯合的細胞毒殺效果在小細胞肺癌之研究

Abstract

肺癌(lung cancer)位居全世界的癌症死因之首。其中的小細胞肺癌(small cell lung cancer)占所有肺癌的百分之十三，而且比例有逐漸下降的趨勢，然而儘管如此它卻是所有肺癌裡面最具侵略性的一種。雖然小細胞肺癌對於第一線化學治療初始有良好的反應，但許多小細胞肺癌的病患仍然有很高的機會復發，甚至五年存活率只有大概百分之五。此外，在第一線化學治療療程結束後所使用的維持治療大部份都不太有效。因此，小細胞肺癌仍然需要發展嶄新的治療策略。胸腺嘧啶核苷酸合成酶(thymidylate synthase)是去氧核醣核酸(DNA)全新合成路徑的關鍵酵素，然而有研究指出胸腺嘧啶核苷酸合成酶的高表現量和造成小細胞肺癌病患較差的存活率有正相關聯。而許多的胸腺嘧啶核苷酸合成酶抑制劑被嘗試使用在小細胞肺癌治療的臨床研究上。但儘管如此，小細胞肺癌即使施以胸腺嘧啶核苷酸合成酶抑制劑5-氟尿嘧啶(5-fluorouracil)仍然展現出胸腺嘧啶核苷酸合成酶的高表達量由於其抗藥性。為了改善小細胞肺癌對於5-氟尿嘧啶的抗藥性，我們將組織蛋白去乙醯酶(histone deacetylase)抑制劑伏立諾他(vorinostat)和5-氟尿嘧啶合併使用。我們的結果顯示，這兩種藥物合併使用可以提升其對H209小細胞肺癌的細胞毒殺性以及促進細胞凋亡，甚至還克服了對於5-氟尿嘧啶的抗藥性。此外，我們也發現MAPK/ERK訊息傳遞路徑對於這兩種藥物合併使用所造成的促進細胞凋亡可能是個影響的關鍵。而在活體內的研究，這兩種藥物合併使用在異體移植H209小細胞肺癌的動物模式中對於抑制腫瘤生長上有良好的協同效果，然而這個結果和活體外細胞實驗的結果可以互相呼應。總結來說，我們的結果有助於未來在治療小細胞肺癌上以伏立諾他和5-氟尿嘧啶的組合藥物設計，提供一個方便於口服的新型維持治療方式。

Lung cancer is leading case of cancers related death in worldwide. Small cell lung cancer (SCLC) accounts for 13% of all lung cancer cases and tends to decline annually, and then it is aggressive subtype of lung cancer. Although initial treatment regimen of SCLC has high sensitive response for standard first line chemotherapeutic drugs, many SCLC patients still have high possibility of tumor relapse, and then even 5-year survival rate of patients only have approximately 5%. Furthermore, most of maintenance therapies aren’t powerful after end of first line treatment regimen. Therefore, the novel therapeutic strategies still need to develop. Thymidylate synthase (TS) is an important enzyme in de novo DNA synthetic pathway, and then is reported high levels of TS expression correlates with poor survival rate of SCLC patients. There are many TS inhibitors are tried using for SCLC therapy in clinical tumor studies. However, TS inhibitor 5-fluorouracil (5-FU) performs high levels of TS expression due to drug resistance in SCLC treatment. To improve 5-FU resistance for SCLC, we use histone deacetylase (HDAC) inhibitor vorinostat (SAHA) to combine with 5-FU. Our results showed combination of SAHA and 5-FU could enhance cell toxicity and induce cell apoptosis, and then even overcame drug resistance of 5-FU in H209 SCLC cell lines. Furthermore, we also found MAPK/ERK pathway might play an important role in cell apoptosis induction after combination treatment. In our in vivo studies, this combination treatment had well anti-cancer effects on inhibition of tumor growth in H209 xenografts animal models, and then was consistent with our in vitro results. In summary, our results suggest SAHA in combined with 5-FU may provide new maintenance therapy with convenience for oral administration for SCLC therapy in future.