Differential sensitivity of double minute chromosomes to hydroxyurea treatment in cultured methotrexate-resistant mouse cells

Mutation Research/Mutation Research Genomics Pub Date : 1999-08-01 DOI:10.1016/S1383-5726(98)00010-7

Barbara H. Nevaldine, Rabia Rizwana, Peter J. Hahn

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引用次数: 7

Abstract

Treating mammalian cells with continuous sub-lethal doses of Hydroxyurea (HU) causes the loss of double minute chromosomes (DMs) containing amplified oncogenes in culture. Recently, we have shown that treating glioblastoma multiforme cells in culture with low doses of HU causes the loss of DMs containing epidermal growth factor receptor genes. Loss of amplified EGFR genes was accompanied by cessation of growth, and greatly decreased tumorigenicity. To further study HU-induced elimination of DMs we have now followed the fate of dihydrofolate reductase gene (DHFR) amplifying DMs in methotrexate-resistant mouse cells during simultaneous treatment with both MTX and HU. We report that in the presence of both HU and MTX, the amplified genes decreased to 25% of starting levels in the first week of treatment, but that ultimately the cells become resistant to HU and reamplify the DHFR gene. We also report that some DHFR amplifying DMs are much more sensitive to HU than others. This study demonstrates that HU does not simply increase the rate of passive loss of DMs.

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培养的甲氨蝶呤耐药小鼠细胞双分钟染色体对羟基脲处理的差异敏感性

用连续亚致死剂量的羟基脲(HU)处理哺乳动物细胞会导致培养中含有扩增致癌基因的双分钟染色体(DMs)的丢失。最近，我们发现用低剂量的HU治疗培养的胶质母细胞瘤多形性细胞会导致含有表皮生长因子受体基因的dm的丢失。EGFR扩增基因的丢失伴随着生长停止，并大大降低了致瘤性。为了进一步研究甲氨蝶呤诱导的DMs消除，我们现在在甲氨蝶呤和甲氨蝶呤同时治疗的小鼠细胞中观察了二氢叶酸还原酶基因(DHFR)扩增DMs的命运。我们报道，在同时存在HU和MTX的情况下，在治疗的第一周，扩增的基因下降到起始水平的25%，但最终细胞对HU产生耐药性并重新扩增DHFR基因。我们还报道了一些DHFR扩增dm对HU的敏感性比其他dm高得多。本研究表明，HU并不是简单地增加dm的被动损失率。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Mutation Research/Mutation Research Genomics

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