Survey of cytotoxicities and antimutagenic and antitumor initiating activities of Cu(II)(3,5-diisopropylsalicylate)2 and its analogs in a keratinocyte-mediated mutation assay and the murine skin multistage carcinogenesis model.

Survey of cytotoxicities and antimutagenic and antitumor initiating activities of Cu(II)(3,5-diisopropylsalicylate)2 and its analogs in a keratinocyte-mediated mutation assay and the murine skin multistage carcinogenesis model.
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Cu(II)(3,5-二异丙基水杨酸酯)2 及其类似物在角质形成细胞介导的突变测定和小鼠皮肤多阶段癌变模型中的细胞毒性、抗突变和抗肿瘤起始活性的调查。

DOI:
10.1093/carcin/9.4.629
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发表时间:
1988
期刊:
影响因子:
4.7
通讯作者:
Colby,AB
Colby,AB
中科院分区:
医学2区
文献类型:
--
作者:
ReinersJr,JJ;Colby,AB

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角质形成细胞介导的致突变试验和小鼠皮肤多阶段癌变肿瘤模型被用来调查Cu(II)(3,5-二异丙基水杨酸)2[CuDIPS]及其类似物的化学预防特性。补充新生SENCAR角质形成细胞和中国仓鼠肺成纤维细胞的共培养物(V79细胞)与CuDIPS、3,5-二异丙基水杨酸(DIPS)和CuSO 4的联合作用导致V79细胞的剂量依赖性杀伤(LD 50分别为34、75、960 μM),并抑制苯并[a]芘(BP)和7,12-二甲基苯并[a]蒽(DMBA)致突变(ED 50分别为13、95、80 μM和40、125、110μM)。剂量-反应曲线分析表明:CuDIPS对DMBA的抗突变活性和铜配合物的细胞毒性来自于螯合物中的DIPS组分; CuDIPS对BP的抗突变活性需要铜和DIPS; CuDIPS和CuDIPS诱导的细胞毒性是抑制突变的必要条件。CuDIPS的诱变抑制不介导的前诱变剂代谢的调制,因为抗诱变浓度的螯合物DMBA和BP依赖的细胞毒性没有显着的影响。在用DMBA或BP开始之前用CuDIPS(100-4000 nmol)局部预处理SENCAR小鼠15 mm,导致在20周的促进后乳头状瘤/小鼠的小的(最大38%)非剂量响应性减少。
A keratinocyte-mediated mutagenesis assay, and the murine skin multistage carcinogenesis tumor model were used to survey the chemopreventive properties of Cu(II)(3,5-diiso-propylsalicylate)2[CuDIPS] and its analogs. Supplementation of cocultures of newborn SENCAR keratinocytes and Chinese hamster lung fibroblasts (V79 cells) with CuDIPS, 3,5-diisopropylsalicylate (DIPS), and CuSO4resulted in dose-dependent killings of V79 cells (LD50of 34, 75, 960 μM, respectively), and inhibitions of benzo [a]pyrene (BP) and 7,12-dimethylbenz[a]anthracene (DMBA) mutagenesis (ED50of 13, 95, 80 μM, and 40, 125, 110μM, respectively). Analyses of dose-response curvessuggest (i) CuDIPS preferentially in hibits BP mutagenesis; (ii) the antimutagemc activity of CuDIPS towards DMBA and the cytotoxicity of the copper complex are derived from the DIPS component of the chelate; (iii) the antimutagenic activity of CuDIPS towards BP requires both copper and DIPS; and (iv) DIPS and CuDIPS induced cytotoxicity is required for inhibition of mutagenesis. Inhibition of mutagenesis by CuDIPS was not mediated by modulation of promutagen metabolism because antimutagenic concentrations of the chelate had no significant effects on DMBA- and BP-dependent cytotoxicities. Topical pretreatment of SENCAR mice with CuDIPS (100–4000 nmol) 15 mm prior to initiation with DMBA or BP resulted in small (38% maximum) non-dose-responsive reductions of papillomas/mouse following 20 weeks of promotion.
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