Synergistic Study of Drug Resistance Modulators on the Chemocytotoxicity to Transitional Cell Carcinoma

對移形上皮細胞癌多重抗藥性之修飾調降研究

于大雄(Dah-Shyong Yu) ； 陳宏一(Hong-I Chen) ； 張聖原(Sun-Yran Chang)

《臺灣泌尿科醫學會雜誌》 14卷4期 (2003/12) Pp. 168-175

摘要

研究目的：內生性多重抗藻性是晚期移形上皮細胞癌有效化學治療之主要障礙。本研究主要目的乃在測試各種修飾劑移形上皮細胞癌化學治療毒殺作用之加強效果。
材料與方法：各種抗癌藥物包括 adriarnycin 及 cisplatin 被用於測試對移形上皮細胞癌細胞株之毒殺。共使用14種修飾劑，包括鈣離子拮抗劑、丙種蛋白動力酵素抑制劑、胱胺酸轉化酶抑制劑、蛋白／胜 合成抑制劑、呼吸鏈抑制劑、去結合劑、ATP合成抑制劑及親離子劑，利用微量 tetrazolium 法測試其拮抗多重抗藥性之能力。動物腫瘤模式也被用於評估這些修飾劑之組合是否也可加強抗癌藥物對腫瘤之生長抑制。
結果：研究顯示 verapamil, quinidine, tamoxifen, oligomycin 及 ouabain皆有明顯之加強 adriarnycin 對移形上皮細胞癌毒殺作用。加強作用與修飾劑作用劑量及時間相關。進一步綜合使用這幾種修飾劑並未見更強之毒殺作用。動物研究顯示 verapami 可加強 adriarnycin 對皮下腫瘤生長之抑制。
結論：鈣離子拮抗劑（verapamil），tamoxifen, oligomycin 及 ouabain 可分別單獨使用於移形上皮細胞癌之輔助性化學治療，至於有關各種修飾劑結合性治療所使用之方式、時間及劑量仍有待進一步探討。

關鍵字

移形上皮細胞癌 ； 多重性抗藥性 ； 修飾劑 ； 鈣離子拮抗劑 ； tamoxifen

並列摘要

OBJECTIVE: Intrinsic multi drug resistance (MDR) is a major obstacle for effective chemotherapy of advanced transitional cell carcinoma (TCC). The aim of this study was to determine he modulation of cytotoxicity of chemotherapeutic drugs on Tee cells by various modulators.
MATERIALS AND METHODS: The cytotoxicities of various anticancer drugs, including adriamycin and cisplatin, to TCC cell lines were analyzed. Fourteen modulators, including calcium antagonists, a protein kinase C inhibitor, a glutathione transferase inhibitor, protein/peptide synthesis inhibitors, respiratory chain inhibitors, an uncoupling reagent, an ATP synthesis inhibitor, and ionophores, were examined for their MDR-reversing activity using the microplate tetrazolium test. An in vivo animal study was conducted to evaluate the synergistic effect on tumor growth of modulators of chemotherapeutic agents.
RESULTS: Results demonstrated that verapamil, quinidine, tamoxifen, oligomycin, and ouabain had prominent synergistic effects on the cytotoxicity of adriamycin to TCC tumor cells. The enhancement was related to the dosage and treatment duration of the modulators. Further trials on simultaneous additions of these modulators to cocktail mixtures showed no higher synergistic effect. An in vivo study showed that verapamil could enhance the suppression of inoculated tumor growth in mice by adriamycin
CONCLUSIONS: The calcium antagonists, tamoxifen, oligomycin, and ouabain, can individual/y be provided as effective adjunctive chemotherapy for overcoming native drug resistance in TCC cells. Combination regimens need more study to determine the optimal administration timing, dosage, and frequency of modulators.

並列關鍵字

transitional cell carcinoma ； multidrug resistance ； modulation ； calcium antagonist ； tamoxifen