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首页> 外文期刊>Pharmacological research: The official journal of The Italian Pharmacological Society >Inhibition of cell proliferation, cytotoxicity and induction of apoptosis of 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene in gastrointestinal tumour cell lines and preliminary evaluation of its toxicity in vivo.
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Inhibition of cell proliferation, cytotoxicity and induction of apoptosis of 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene in gastrointestinal tumour cell lines and preliminary evaluation of its toxicity in vivo.

机译：1,4-双（1-萘基）-2,3-二硝基-1,3-丁二烯在胃肠道肿瘤细胞系中的细胞增殖抑制，细胞毒性和凋亡诱导及其体内毒性的初步评估。

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Our preliminary data suggested that 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene [Viale M, Ottone M, Chiavarina B, Mariggio MA, Prevosto C, Dell'Erba C, et al. Preliminary evaluation in vitro of the inhibition of cell proliferation, cytotoxicity and induction of apoptosis by 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene. Invest New Drug 2004;22:359-67] (Naph-DNB), possesses good characteristics in terms of inhibition of cell proliferation in two cell lines derived from colon and gastric cancers. On this basis and to confirm the specificity of our compound towards gastrointestinal malignancies, we have analyzed the inhibition of cell proliferation, the cytotoxicity and the induction of apoptosis by Naph-DNB in seven cell lines derived from human colon (DLD-1, Lovo, HCT-8 and Colo 741), stomach (HGC-27) and pancreas (Panc-1 and Hup-T4) tumours. For the sake of comparison, cells have also been exposed to four anticancer drugs utilized for the treatment of gastrointestinal malignancies (oxaliplatin, irinotecan, gemcitabine and 5-fluorouracil). Moreover, toxicological data have been obtained in order to define the lethal dose (LD) and maximal tolerated dose (MTD) values and the spectrum of tissue alterations caused by the intraperitoneal (i.p.) and intravenous (i.v.) administration of Naph-DNB. IC50 data obtained by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay suggest that Naph-DNB is generally more active than two or more of the anticancer drugs above in most cell lines: it displayed the lowest activity only in HGC-27 cells, although data concerning the IC75 parameter enlighten a significantly better activity than irinotecan and 5-fluorouracil. Using the equitoxic concentrations IC50 and IC75, we have also evaluated the ability of Naph-DNB and of the other anticancer drugs to kill cells and to induce apoptosis. Our data show that at these concentrations Naph-DNB has a cytotoxic activity comparable or even better than that of some anticancer drugs. Similarly, Naph-DNB induces apoptosis better than the other anticancer drugs in HCT-8 and HGC-27 cells, while in Lovo and Panc-1 cells the induction is comparable. On the basis of toxicological data we defined the LD10, LD50, LD90 (i.p., 17.6, 36.1 and 54.1 mg kg(-1), respectively; i.v., 6.1, 14.1 and 22.0 mg kg(-1), respectively) and the MTD (i.p., 15 mg kg(-1); i.v., 5 mg kg(-1)) parameters. Histochemical analysis has shown that, in general, the administration of even toxic doses of Naph-DNB does not cause great structural injuries, although it can have some effects on the metabolism of glicogen and iron in organs as liver and spleen. In conclusion, our preclinical studies in vitro suggest that Naph-DNB may represent a good anticancer compound for the treatment of generally unresponsive tumours such as those of pancreas, stomach and colon. Moreover, the analysis of its toxic effects has allowed the definition of LD and MTD parameters, which will be used in further experiments in vivo for the definition of its antitumour activity.
机译：我们的初步数据表明，1,4-双（1-萘基）-2,3-二硝基-1,3-丁二烯[Viale M，Ottone M，Chiavarina B，Mariggio MA，Prevosto C，Dell'Erba C等。 1,4-双（1-萘基）-2,3-二硝基-1,3-丁二烯对细胞增殖，细胞毒性和凋亡诱导的体外初步评价。 Invest New Drug 2004; 22：359-67]（Naph-DNB）在抑制源自结肠癌和胃癌的两种细胞系中的细胞增殖方面具有良好的特性。在此基础上，并确认我们的化合物对胃肠道恶性肿瘤的特异性，我们分析了Naph-DNB在源自人类结肠的7种细胞系中对细胞增殖的抑制，细胞毒性和对细胞凋亡的诱导作用（DLD-1，Lovo， HCT-8和Colo 741），胃癌（HGC-27）和胰腺癌（Panc-1和Hup-T4）。为了进行比较，还使细胞暴露于四种用于治疗胃肠道恶性肿瘤的抗癌药物（奥沙利铂，伊立替康，吉西他滨和5-氟尿嘧啶）。而且，已经获得了毒理学数据，以便确定由腹膜内（i.p.）和静脉内（i.v.）施用Naph-DNB引起的致死剂量（LD）和最大耐受剂量（MTD）值以及组织改变的频谱。通过MTT [3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑鎓溴化物]分析获得的IC50数据表明，在大多数细胞中，Naph-DNB通常比上述两种或多种抗癌药更具活性线：仅在HGC-27细胞中显示最低的活性，尽管有关IC75参数的数据显示比伊立替康和5-氟尿嘧啶具有更好的活性。使用同等浓度的IC50和IC75，我们还评估了Naph-DNB和其他抗癌药杀死细胞并诱导凋亡的能力。我们的数据表明，在这些浓度下，Naph-DNB的细胞毒性活性与某些抗癌药物相当甚至更好。同样，在HCT-8和HGC-27细胞中，Naph-DNB诱导的凋亡优于其他抗癌药物，而在Lovo和Panc-1细胞中，诱导作用相当。根据毒理学数据，我们定义了LD10，LD50，LD90（分别为ip，17.6、36.1和54.1 mg kg（-1）; iv，6.1、14.1和22.0 mg kg（-1））和MTD （ip，15 mg kg（-1）; iv，5 mg kg（-1））参数。组织化学分析表明，一般而言，即使对中毒剂量的Naph-DNB给药，也不会对肝脏和脾脏等器官中的胶原蛋白和铁的代谢产生一定的影响，即使对中枢神经系统造成严重损害。总之，我们的体外临床前研究表明，Naph-DNB可能代表一种良好的抗癌化合物，用于治疗一般无反应的肿瘤，例如胰腺，胃和结肠癌。此外，对其毒性作用的分析已经允许定义LD和MTD参数，这些参数将用于体内进一步的实验中以定义其抗肿瘤活性。

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