Intrinsic cellular resistance to oxazaphosphorines exhibited by a human colon carcinoma cell line expressing relatively large amounts of a class-3 aldehyde dehydrogenase.
Intrinsic cellular resistance to oxazaphosphorines exhibited by a human colon carcinoma cell line expressing relatively large amounts of a class-3 aldehyde dehydrogenase.
复制标题
表达相对大量的 3 类醛脱氢酶的人结肠癌细胞系表现出对氧杂磷酸的内在细胞抗性。
DOI：
10.1016/0006-2952(94)90593-2
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发表时间：
1994
影响因子：
5.8
通讯作者：
Sladek,NE
中科院分区：
文献类型：
--
作者：
Rekha,GK;Sreerama,L;Sladek,NE
鉴定了一种培养的人结肠癌细胞系，即结肠C，其表现出由相对升高水平的胞质3类醛脱氢酶介导的对马磷酰胺的内在细胞抗性。发现结肠C细胞的敏感性低得多/耐药性高得多与其他两种培养的人结肠癌细胞系即RCA和HCT 116 b相比，在RCA和HCT 116 b细胞中，NADP依赖性酶催化苯甲醛氧化为苯甲酸，结肠C细胞中的NADP依赖性酶催化苯甲醛氧化为苯甲酸，结肠C细胞中的NADP依赖性酶催化苯甲醛氧化为苯甲酸。这三种细胞系对磷酰胺芥均具有同等敏感性。乙醛脱氢酶活性仅限于结肠C细胞的胞浆（以及在其他两种细胞系中），并且基于其物理、免疫和催化特性，判断起作用的酶是1型ALDH-3，其与甲基胆蒽处理的人乳腺癌MCF-7/0细胞中表达的1型ALDH-3相同，并且与1型ALDH-3非常接近相同。3在人正常胃粘膜中表达。在这些细胞中未发现1类和2类醛脱氢酶。当在苯甲醛或4-（二乙基氨基）苯甲醛（各自为ALDH-3的相对良好底物）存在下暴露于马磷酰胺时，未观察到结肠C细胞部分对马磷酰胺的相对不敏感性，而当在乙醛（该酶的相对较差底物）存在下暴露于马磷酰胺时，保留了对马磷酰胺的相对不敏感性。对马磷酰胺的敏感性HCT 116 b和RCA细胞的一部分，和磷酰胺氮芥的一部分，所有三个细胞系，不受药物暴露时，在任何三种醛的存在下。连同我们实验室的早期报告，这些观察结果表明，内在的，以及稳定的和短暂的获得性，氧氮磷，如马磷酰胺和环磷酰胺的耐药性，可以介导的相对增加水平的胞质3类醛脱氢酶。
A cultured human colon carcinoma cell line, viz. colon C, exhibiting intrinsic cellular resistance to mafosfamide mediated by relatively elevated levels of a cytosolic class-3 aldehyde dehydrogenase was identified. Colon C cells were found to be much less sensitive/more resistant (about 10-fold as judged bylc90values) to mafosfamide than were two other cultured human colon carcinoma cell lines, viz. RCA and HCT 116b, and, as compared to the barely detectable dehydrogenase activity (NADP-dependent enzyme-catalyzed oxidation of benzaldehyde to benzoic acid) in RCA and HCT 116b cells, that in colon C cells was about 200-fold greater. The three cell lines were equisensitive to phosphoramide mustard. Aldehyde dehydrogenase activity was confined to the cytosol in colon C cells (as well as in the other two cell lines) and, on the basis of its physical, immunological and catalytic characteristics, the operative enzyme was judged to be a Type-1 ALDH-3 identical to the Type-1 ALDH-3 expressed in methylcholanthrene-treated human breast adenocarcinoma MCF-7/0 cells and very nearly identical to the Type-1 ALDH-3 expressed in human normal stomach mucosa. Class-1 and class-2 aldehyde dehydrogenases were not found in these cells. The relative insensitivity to mafosfamide on the part of colon C cells was not observed when exposure to mafosfamide was in the presence of benzaldehyde or 4-(diethylamino)benzaldehyde, each a relatively good substrate for ALDH-3, whereas it was retained when exposure to mafosfamide was in the presence of acetaldehyde, a relatively poor substrate for this enzyme. Sensitivity to mafosfamide on the part of HCT 116b and RCA cells, and to phosphoramide mustard on the part of all three cell lines, was unaffected when drug exposure was in the presence of any of the three aldehydes. Together with earlier reports from our laboratory, these observations demonstrate that intrinsic, as well as stable and transient acquired, resistance to oxazaphosphorines, such as mafosfamide and cyclophosphamide, can be mediated by relatively increased levels of cytosolic class-3 aldehyde dehydrogenases.