INTRACELLULAR CARBOXYL ESTERASE-ACTIVITY IS A DETERMINANT OF CELLULAR-SENSITIVITY TO THE ANTINEOPLASTIC AGENT KW-2189 IN CELL-LINES RESISTANT TO CISPLATIN AND CPT-11
INTRACELLULAR CARBOXYL ESTERASE-ACTIVITY IS A DETERMINANT OF CELLULAR-SENSITIVITY TO THE ANTINEOPLASTIC AGENT KW-2189 IN CELL-LINES RESISTANT TO CISPLATIN AND CPT-11
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DOI：
10.1111/j.1349-7006.1995.tb02997.x
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发表时间：
1995-01-01
期刊：
影响因子：
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通讯作者：
SAIJO, N
中科院分区：
文献类型：
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作者：
OGASAWARA, H;NISHIO, K;SAIJO, N
KW-2189是一种新型抗肿瘤抗生素，属于duocarmycin，在羧基酯酶激活后具有显著的dna结合活性，其活性形式DU-86。KW-2189、DU-86和duocarmycin SA对顺铂（CDDP）耐药的人非小细胞肺癌细胞株PC-9/CDDP和PC-14/CDDP以及多药耐药的人小细胞肺癌细胞株H69/VP均有活性。然而，HAC2/0.1，一种耐cddp的人卵巢癌细胞系，由于CPT-11的细胞内活化降低，也对CPT-11耐药，对KW-2189的耐药性约为12.8倍。与亲本细胞系HAC2相比，HAC2/0.1对其他duocarmycin没有耐药性。在KW-2189的细胞内积累方面，HAC2和HAC2/0.1之间没有差异。在培养基中添加130 mU/ml羧基酯酶对HAC2细胞对KW-2189的敏感性没有影响，但HAC2/0.1细胞对KW-2189的敏感性提高到HAC2的水平，说明HAC2/0.1对KW-2189的激活作用不如HAC2， HAC2/0.1的全细胞和微体提取物的羧基酯酶活性约为HAC2的60%。无细胞实验表明，在HAC2存在下，KW-2189比HAC2/0.1细胞提取物更有效地与DNA结合。由此可见，HAC2/0.1细胞胞内羧基酯酶活性降低导致细胞内KW-2189向活性形式转化减少，从而产生对KW-2189的抗性。HAC2/0.1细胞中CPT-11向SN-38转化的减少可能与羧基酯酶活性降低有关。
KW-2189, a novel antitumor antibiotic belonging to the duocarmycins, possesses marked DNA-binding activity upon activation by carboxyl esterase to its active form, DU-86. Three duocarmycins, KW-2189, DU-86 and duocarmycin SA, were active against the cisplatin (CDDP)-resistant human non-small cell lung cancer cell lines PC-9/CDDP and PC-14/CDDP, and the multidrug-resistant human small cell lung cancer cell line H69/VP. However, HAC2/0.1, a CDDP-resistant human ovarian cancer cell line which is also resistant to CPT-11 because of decreased intracellular activation of CPT-11, was about 12.8-fold more resistant to KW-2189. HAC2/0.1 was not resistant to other duocarmycins as compared to its parental cell line, HAC2. There was no difference between HAC2 and HAC2/0.1 with regard to the intracellular accumulation of KW-2189. Addition of 130 mU/ml of carboxyl esterase to the culture medium did not influence the sensitivity of HAC2 cells to KW-2189, However, the sensitivity of HAC2/0.1 cells to KW-2189 was enhanced to the level of HAC2, These results suggest that HAC2/0.1 is less potent than HAC2 in activating KW-2189, The carboxyl esterase activity of whole-cell and microsomal extracts from HAC2/0.1 was approximately 60% of that from HAC2. The cell-free experiment revealed that KW-2189 bound to DNA more efficiently in the presence of HAC2 than HAC2/0.1 cell extract. It was concluded that decreased intracellular carboxyl esterase activity in HAC2/0.1 cells caused decreased intracellular conversion of KW-2189 to its active form, thus producing resistance to KW-2189. The decreased conversion of CPT-11 to SN-38 in HAC2/0.1 cells might be explained by decreased carboxyl esterase activity.