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首页> 外文期刊>Journal of Medicinal Chemistry >Cyclopropane-Containing Polyamine Analogues Are Efficient Growth Inhibitors of a Human Prostate Tumor Xenograft in Nude Mice
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Cyclopropane-Containing Polyamine Analogues Are Efficient Growth Inhibitors of a Human Prostate Tumor Xenograft in Nude Mice

机译：含环丙烷的多胺类似物是裸鼠中人前列腺肿瘤异种移植物的有效生长抑制剂。

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Polyamine analogues 7, 10, 18, 27, and 32 containing cyclopropane rings were obtained by chemical synthesis. Their antineoplastic activities were assessed against the cultured human prostate tumor cell lines DU-145, DuPro, and PC-3. Decamines 32 and 27 exhibited variable levels of cytotoxicity against all three cell lines, while 7, 10, and 18 were efficacious against DU-145 and DuPro. Maximum tolerated doses (MTD) for all five compounds in a NCr-nu mouse model were determined at dosing schedules of q1d * 5 (ip) in two cycles with a break of 10 days between cycles. Their antitumor efficacies were then tested against DU-145 tumor xenografts in mice treated with all five agents at their respective MTDs. In addition, the efficacies of 7 and 10 against the same tumor xenograft were assessed at doses below their respective MTDs. In all experiments, administration began two weeks after tumor implantation. All compounds efficiently inhibited tumor growth for up to 50 days postimplantation, with negligible animal body weight loss. Tetramine 10 and hexamine 18 were the most efficient among the five analogues in arresting tumor growth. Tetramine 10 containing two cyclopropane rings had the lowest systemic toxicity as reflected in animal body weight loss. It was further assessed at a weekly administration regimen of (q1w * 4) in two cycles with a four-week break between the cycles. At this dosing schedule, 10 again efficiently arrested tumor growth with negligible effect on animal body weight. Tetramine 10 also arrested the growth of large tumors (ca. 2000 mm~3) treated 66 days postimplantation. Studies on the metabolism of 10 showed that it accumulates in tumor within 6 h after the end of administration and reached a maximum level 72 h after cessation of dosing. Intracellular concentrations of 10 in liver and kidney were much smaller when compared to those in the tumor when measured 72 h after cessation of dosing. In liver and kidney, the deethyl metabolites of 10 accumulated over a 96 h period after cessation of dosing.
机译：通过化学合成获得了含有环丙烷环的多胺类似物7、10、18、27和32。针对培养的人前列腺肿瘤细胞系DU-145，DuPro和PC-3评估了它们的抗肿瘤活性。癸胺32和27对所有三种细胞系均表现出不同程度的细胞毒性，而7，10和18对DU-145和DuPro有效。在NCr-nu小鼠模型中，以q1d * 5（ip）的给药方案在两个周期中确定所有五种化合物的最大耐受剂量（MTD），每个周期之间间隔10天。然后在用各自的MTD用所有五种药物治疗的小鼠中测试了它们对DU-145肿瘤异种移植物的抗肿瘤功效。另外，以低于它们各自MTD的剂量评估了7和10对相同肿瘤异种移植物的功效。在所有实验中，在肿瘤植入后两周开始给药。所有化合物均可在植入后长达50天的时间内有效抑制肿瘤生长，且动物体重减轻可忽略不计。在阻止肿瘤生长的五种类似物中，四胺10和己胺18是最有效的。从动物体重减轻中可以看出，含有两个环丙烷环的四胺10具有最低的全身毒性。在两个周期的每周一次给药方案（q1w * 4）中进行了进一步评估，两个周期之间有四个星期的间隔。在该给药方案中，有10只再次有效地阻止了肿瘤的生长，而对动物体重的影响可忽略不计。 Tetramine 10还阻止了植入后66天处理的大肿瘤（约2000 mm〜3）的生长。对10的代谢的研究表明，它在给药结束后6小时内在肿瘤中蓄积，并在停止给药后72小时达到最高水平。与停止给药后72小时测量的肿瘤中的浓度相比，肝和肾中的细胞内浓度10要小得多。在肝和肾中，停止给药后的96小时内会累积10种脱乙基代谢产物。

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