Potentiation of carcinogen-induced methotrexate resistance and dihydrofolate reductase gene amplification by inhibitors of poly(adenosine diphosphate-ribose) polymerase.
Potentiation of carcinogen-induced methotrexate resistance and dihydrofolate reductase gene amplification by inhibitors of poly(adenosine diphosphate-ribose) polymerase.
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通过聚（腺苷二磷酸核糖）聚合酶抑制剂增强致癌物诱导的甲氨蝶呤抗性和二氢叶酸还原酶基因扩增。
作者：
A. Bürkle;R. Heilbronn;H. zur Hausen
核蛋白的聚（adp -核糖基）化是大多数真核细胞对DNA链断裂的直接反应，如致癌物治疗引起的。另一方面，DNA扩增也可以在细胞培养系统中被化学或物理致癌物诱导，在诱导治疗后几天达到峰值。我们之前已经证明，聚（adp -核糖基）化抑制剂3-氨基苯甲酰胺在仓鼠细胞中作为短期模型系统，增强了致癌物质诱导的猿猴病毒40 DNA扩增（b<s:1> rkle等人，癌症研究，47:3632- 3636,1987）。在这里，我们报告这些结果可以扩展到甲氨蝶呤（MTX）耐药性的发展与二氢叶酸还原酶（DHFR）基因扩增在不同的仓鼠细胞系。(a)选择前3天用350 nM MTX处理烷基化致癌物n -甲基-n′-硝基-n -亚硝基胍（MNNG）， MTX抗性频率达到预期的17- 100倍。在MNNG治疗前添加3-氨基苯甲酰胺（0.1至1mm），以剂量依赖的方式进一步增强MTX耐药频率，最多可达5倍，与细胞毒性增强相似。MTX耐药频率不仅相对于细胞存活率的降低而增强，而且在绝对值上也增强。在排除直接药物相互作用的条件下，与苯甲酰胺（1 mM）（另一种聚（adp -核糖基）化抑制剂）共处理后也发生了相同的增强作用。苯甲酸是一种非抑制性类似物，对mnng诱导的MTX耐药频率没有影响。(b) 3-氨基苯甲酰胺、苯甲酰胺和苯甲酸在1 mM浓度下对甲氨喋呤自发耐药频率均无影响。(c)扩增个体mtx耐药菌落以确定其DHFR基因拷贝数。无论克隆是由MNNG单独诱导还是在存在1mm 3-氨基苯甲酰胺的MNNG诱导的培养物中获得，DHFR基因扩增的相对频率是相似的（14%对22%）。我们得出结论，聚（adp -核糖）化应该是诱导DNA扩增的负调控因子，因为聚（adp -核糖）聚合酶的抑制增强了mnng诱导的猿猴病毒40 DNA扩增（如前所示）和mnng诱导的与DHFR基因扩增相关的MTX抗性（如本文所示）。
Poly(ADP-ribosyl)ation of nuclear proteins is an immediate response of most eukaryotic cells to DNA strand breaks, as induced by carcinogen treatment. DNA amplification, on the other hand, can be induced in cell culture systems by chemical or physical carcinogens, too, reaching peak levels a few days after induction treatment. We have previously shown that 3-aminobenzamide, an inhibitor of poly(ADP-ribosyl)ation, potentiates carcinogen-induced simian virus 40 DNA amplification in hamster cells which served as a short-term model system (Bürkle et al., Cancer Res., 47: 3632-3636, 1987). Here we report that those results can be extended to the development of methotrexate (MTX) resistance associated with dihydrofolate reductase (DHFR) gene amplification in a different hamster cell line. (a) Treatment with the alkylating carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) 3 days before selection with 350 nM MTX induced the MTX resistance frequency by 17- to 100-fold, as expected. Addition of 3-aminobenzamide (0.1 to 1 mM) before MNNG treatment further potentiated the frequency of MTX resistance by up to 5-fold in a dose-dependent manner, parallel to a potentiation of cytotoxicity. MTX resistance frequency was potentiated not only relative to the decrease in cell survival but also in absolute terms. The same potentiation occurred after cotreatment with benzamide (1 mM), another poly(ADP-ribosyl)ation inhibitor, under conditions which precluded direct drug interactions. Benzoic acid, a noninhibitory analogue, had no effect on the MNNG-induced MTX resistance frequency. (b) Neither 3-aminobenzamide, nor benzamide, nor benzoic acid at 1 mM, respectively, had any effect on the spontaneous frequency of MTX resistance. (c) Individual MTX-resistant colonies were expanded to determine their DHFR gene copy number. The relative frequency of DHFR gene amplification was similar (14% versus 22%) whether clones were derived from cultures induced with MNNG alone or MNNG in the presence of 1 mM 3-aminobenzamide. We conclude that poly(ADP-ribosyl)ation should act as a negative regulatory factor in the induction of DNA amplification, since inhibition of poly(ADP-ribose) polymerase potentiates both MNNG-induced simian virus 40 DNA amplification, as shown previously, and MNNG-induced MTX resistance associated with DHFR gene amplification, as shown in this paper.
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DOI：
10.1073/pnas.83.16.5978
发表时间：
1986-08-01
影响因子：
11.1
作者：
RICE, GC;HOY, C;SCHIMKE, RT
通讯作者：
SCHIMKE, RT
ADP-核糖基化抑制剂的体外和体内定量研究。
DOI：
--
发表时间：
1989
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Rankin,PW;Jacobson,EL;Benjamin,RC;Moss,J;Jacobson,MK
通讯作者：
Jacobson,MK
伽马射线辐射增强中国仓鼠卵巢和小鼠 3T6 细胞对甲氨蝶呤耐药的频率。
影响因子：
11.2
作者：
Sharma,RC;Schimke,RT
通讯作者：
Schimke,RT
影响因子：
56.9
作者：
SLAMON, DJ;CLARK, GM;MCGUIRE, WL
通讯作者：
MCGUIRE, WL
DOI：
10.1007/978-1-60327-461-6_11
发表时间：
2009
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Cassany, Aurelia;Gerace, Larry
通讯作者：
Gerace, Larry