Jansen W J, Zwart B, Hulscher S T, Giaccone G, Pinedo H M, Boven E
Department of Medical Oncology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Int J Cancer. 1997 Jan 27;70(3):335-40. doi: 10.1002/(sici)1097-0215(19970127)70:3<335::aid-ijc15>3.0.co;2-e.
CPT-11, a new semisynthetic derivative of camptothecin, is active in a number of tumor types in the clinic, including colon cancer. CPT-11 is a drug that is converted into the active metabolite SN-38 by a carboxylesterase. Experiments were performed to obtain more insight in the cellular characteristics in 5 unselected human colon-cancer cell lines that account for the differential sensitivity to CPT-11 and SN-38. In vitro, the sensitivity to CPT-11 and SN-38 was highest in LS174T and COLO 320 cells, intermediate in SW1398 cells and lowest in COLO 205 and WiDr cells. SN-38 was 130 to 570 times more active than CPT-11. CPT-11 induced complete remissions in 6 out of 12 COLO 320 tumors grown as subcutaneous xenografts, but was not effective in WiDr tumors. The cellular carboxylesterase activity did not relate to the sensitivity to CPT-11. The enzyme activity was higher in normal mouse tissues, i.e., serum and liver, than in COLO 320 or WiDr xenografts, indicating that tumor carboxylesterase is of minor importance for CPT-11 efficacy. The topoisomerase-1 mRNA expression in tumor cells was not predictive of the antiproliferative effects of CPT-11 or SN-38. We observed a positive relationship between the DNA topoisomerase-1 activity and the cellular sensitivity to carboxylesterase-activated CPT-11 (r = 0.75, p < 0.1) as well as to SN-38 (r = 0.89, p < 0.05). The higher topoisomerase-1 activity in COLO 320 cells and tumors when compared with that in WiDr cells and tumors reflected the differences in sensitivity to the drug(s). In conclusion, the DNA topoisomerase-1 activity was the best determinant for CPT-11/SN-38 sensitivity in this panel of unselected human colon-cancer cell lines.
CPT - 11是一种喜树碱的新型半合成衍生物，在临床上对多种肿瘤类型有效，包括结肠癌。CPT - 11是一种经羧酸酯酶转化为活性代谢产物SN - 38的药物。我们进行了实验，以更深入了解5种未经筛选的人类结肠癌细胞系的细胞特征，这些细胞系对CPT - 11和SN - 38的敏感性存在差异。在体外，LS174T和COLO 320细胞对CPT - 11和SN - 38的敏感性最高，SW1398细胞次之，COLO 205和WiDr细胞最低。SN - 38的活性比CPT - 11高130至570倍。CPT - 11使12个作为皮下异种移植物生长的COLO 320肿瘤中的6个完全缓解，但对WiDr肿瘤无效。细胞羧酸酯酶活性与对CPT - 11的敏感性无关。正常小鼠组织（即血清和肝脏）中的酶活性高于COLO 320或WiDr异种移植物，这表明肿瘤羧酸酯酶对CPT - 11疗效的重要性较小。肿瘤细胞中的拓扑异构酶 - 1 mRNA表达不能预测CPT - 11或SN - 38的抗增殖作用。我们观察到DNA拓扑异构酶 - 1活性与细胞对羧酸酯酶激活的CPT - 11（r = 0.75，p < 0.1）以及SN - 38（r = 0.89，p < 0.05）的敏感性之间存在正相关。与WiDr细胞和肿瘤相比，COLO 320细胞和肿瘤中较高的拓扑异构酶 - 1活性反映了对药物敏感性的差异。总之，在这组未经筛选的人类结肠癌细胞系中，DNA拓扑异构酶 - 1活性是CPT - 11/SN - 38敏感性的最佳决定因素。
