子宮頸癌中拓樸酵素Ⅰ活性的升高與喜樹鹼增強放射治療的展現

Elevated Topoisomerase Ⅰ Activity in Cervical Cancer as a Target for Potentiation of Radiotherapy

余慕賢(Mu-Hsien Yu) ； 羅傳倫(Steve R. Roffler)

《中華民國婦癌醫學雜誌》 2001年1期 (2001/04) Pp. 1-15

https://doi.org/10.7010/JGO.200104.0001

摘要

目的：此研究之目的主要在探討抗癌藥物喜樹鹼(Camptothecin)(CPT)之標的物－拓樸酵素Ⅰ(topoisomerase Ⅰ)(topo Ⅰ)在子宮頸癌組織中活性的表現是否增加和用喜樹鹼來治療子宮頸癌是否可以使癌細胞增加對放射治療的敏感性。
方法：以計算將旋轉去氧核醣核甘酸(supercoiled DNA)放鬆(relaxation)的能力當作組織中拓樸酵素Ⅰ的活性，以此來偵測11個正常子宮頸組織和30個子宮頸癌組織。將培養的人類子宮頸癌CaSki細胞株分別於生長中(subconfluent)或長滿飽和後(postconfluent)曝露於喜樹鹼(1-5000ng/ml)和隨即的放射線照射(0-800cGy)，最後以檢測細胞聚落生成的數目來計算細胞的存活情形。
結果：子宮頸癌組織細胞中拓樸酵素Ⅰ的平均活性(3.0±0.06h^(-1))較正常子宮頸組織細胞中的活性(0.29±0.06h^(-1))明顯提高且具有統計上之意義。另外在第三期和第四期的子宮頸癌組識細胞中，拓樸酵素Ⅰ的活性(5.88±3.7h^(-1))表現較第一期和第二期(2.57±0.47h^(-1))高出甚多，呈現依其疾病程度遞增的趨勢。合併喜樹鹼和低劑量放射線照射培養皿生長中的CaSki細胞，可表現出相加性的細胞毒殺效果。合併1或10ng/ml喜樹鹼2或8小時和低劑量放射線（200和400cGy）照射培養皿中已長滿飽和的CaSki細胞，可以產生加成的毒殺效果，較單獨使用個別治劑有更佳的治療效果。
結論：子宮頸癌細胞中的拓樸酵素Ⅰ活性較正常子宮頸細胞中的表現為高。以低濃度喜樹鹼同時加上放射線照射，可以增加不處於細胞分裂週期之癌細胞的放射敏感性，增加癌症的治療效果。

關鍵字

喜樹鹼 ； 拓樸酵素Ⅰ ； 子宮頸癌 ； 放射治療

並列摘要

Objective: The aim of this study was to determine whether the activity of topoisomerase Ⅰ (topo Ⅰ), the target of the anti-neoplastic drug camptothecin (CPT), is elevated in cervical cancer and whether CPT can radiosensitize cervical tumors. Methods: The topo Ⅰ activity of llnormal cervix and 30 cervical carcinoma tumors was assayed by measuring the relaxation of supercoiled DNA. Subconfluent or postconfluent CaSki human cervical carcinoma cells were exposed to CPT (1-5000 n/ml) and immediately X-irradiated (0-800 cGy). Cell survival was determined by clonogenic assay. Results: Mean topo Ⅰ activity in cervical cancer (3.0 ± 0.06 h^(-1)) was significantly greater than normal cervix tissue (0.29±0.06 h^(-1)). Stage 3 and 4 cervical carcinoma specimens displayed a trend of greater topo Ⅰ activity (5.88 ±3.7h^(-1)) than stage 1 and 2 tumors (2.57 ± 0.47 h^(-1)). No correlation between topo Ⅰ protein levels and catalytic activity was found. Combined treatment of subconfluent CaSki cells with CPT and ionizing radiation resulted in additive killing of cells. Combined treatment of postconfluent CaSki cells with low doses of radiation (200 and 400 cGy) and 1 or 10 ng/ml CPT for 2 or 48 h produced significant cytotoxicity compared to CPT or radiation alone, which were ineffective at these doses. Conclusions: Topo Ⅰ activity is elevated in cervical cancer compared to normal cervix. The radiosensitivity of noncycling cells within cervical tumors may be increased by simultaneous treatment with low doses of CPT or other topo I inhibitors

並列關鍵字

camptothecin ； topoisomerase Ⅰ ； cervical carcinoma ； radiotherapy