Relationships among cell survival, O6-alkylguanine-DNA alkyltransferase activity, and reactivation of methylated adenovirus 5 and herpes simplex virus type 1 in human melanoma cell lines.-猫眼课题宝

人黑色素瘤细胞系中细胞存活、O6-烷基鸟嘌呤-DNA 烷基转移酶活性以及甲基化腺病毒 5 型和单纯疱疹病毒 1 型再激活之间的关系。

DOI：

10.1182/blood.v71.5.1487.1487

发表时间：

1989

期刊：

Cancer research

影响因子：

11.2

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

K. Maynard;P. Parsons;T. Cerny;G. Margison

在对抗肿瘤 DNA 甲基化剂 MTIC 杀伤敏感或耐药的人黑色素瘤细胞系中，比较了 5-(3-甲基-1-三氮烯基)咪唑-4-甲酰胺 (MTIC) 甲基化病毒的 O6-烷基鸟嘌呤-DNA 烷基转移酶 (ATase) 活性和宿主细胞再激活 (HCR)。腺病毒5号增强的HCR（定义为Mer+表型）通常与宿主细胞对MTIC毒性作用和ATase活性水平的天然或诱导抗性表现出半定量相关性。然而，我们发现了一种 MTIC 抗性细胞系 (MM170)，其 ATase 水平较低，腺病毒 HCR 处于中等水平。与 Mer- 细胞相比，对 MTIC 具有天然抗性的 Mer+ 细胞中 1 型单纯疱疹病毒 (HSV-1) 的 HCR 增强。另一方面，诱导MTIC抗性的Mer+细胞中HSV-1的HCR与Mer-细胞中相似。腺病毒5和HSV-1感染均不诱导Mer细胞中的ATase活性。这表明对甲基化剂毒性作用的抵抗力并不总是与人类黑色素瘤细胞中高水平的 ATase 活性相关。此外，虽然从 Mer- 细胞诱导 Mer+ 表型通常伴随着 ATase 活性的恢复，但诱导的 Mer+ 细胞的修复能力低于天然 Mer+ 细胞，这通过细胞抵抗力稍低进行定量判断，并通过 HSV-1 的 HCR 反应缺陷进行定性判断。这些结果表明 Mer- 和诱导的 Mer+ 细胞缺乏不依赖于 ATase 的 DNA 修复机制。 Mer-、天然 Mer+ 和诱导 Mer+ 表型之间没有发现 MTIC 诱导的 DNA 修复合成或链断裂存在差异。然而，天然 Mer+ 细胞中紫外线诱导的 DNA 修复合成高于 Mer- 或诱导 Mer+ 细胞，这两种细胞都增加了细胞对抗代谢药物甲氨蝶呤和羟基脲的敏感性。这些差异可能与 MTIC 观察到的效果有关。在人类黑色素瘤活检材料中发现了多种 ATase 活性。

O6-Alkylguanine-DNA alkyltransferase (ATase) activity and host cell reactivation (HCR) of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC)-methylated viruses were compared in human melanoma cell lines that were sensitive or resistant to killing by the antitumor DNA-methylating agent MTIC. Enhanced HCR of adenovirus 5 (defined as the Mer+ phenotype) generally showed a semiquantitative correlation with the natural or induced resistance of the host cells to the toxic effects of MTIC and to the level of ATase activity. However, one MTIC-resistant cell line was found (MM170) which had a low level of ATase and intermediate HCR of adenovirus. The HCR of herpes simplex virus type 1 (HSV-1) was enhanced in the Mer+ cells that had natural resistance to MTIC compared with Mer- cells. On the other hand, HCR of HSV-1 in Mer+ cells with induced resistance to MTIC was similar to that in Mer- cells. Neither adenovirus 5 nor HSV-1 infection induced ATase activity in Mer- cells. This indicates that resistance to the toxic effects of methylating agents is not invariably associated with high levels of ATase activity in human melanoma cells. Furthermore, while induction of the Mer+ phenotype from Mer- cells was usually accompanied by the recovery of ATase activity, induced Mer+ cells had less proficient repair than natural Mer+ cells, as judged quantitatively by slightly lower cellular resistance and qualitatively by deficient HCR response for HSV-1. These results suggest that the Mer- and induced Mer+ cells lack an ATase-independent DNA repair mechanism. No differences in MTIC-induced DNA repair synthesis or strand breaks were found between the Mer-, natural Mer+, and induced Mer+ phenotypes. However, UV-induced DNA repair synthesis was higher in the natural Mer+ than in the Mer- or induced Mer+ cells, both of which had increased cellular sensitivity to the antimetabolites methotrexate and hydroxyurea. These differences may be related to the effects observed with MTIC. A wide range of ATase activities was found in human melanoma biopsy material.

Suppression of human DNA alkylation-repair defects by Escherichia coli DNA-repair genes.