The role of the polyamine catabolic enzymes SSAT and SMO in the synergistic effects of standard chemotherapeutic agents with a polyamine analogue in human breast cancer cell lines.
The role of the polyamine catabolic enzymes SSAT and SMO in the synergistic effects of standard chemotherapeutic agents with a polyamine analogue in human breast cancer cell lines.
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DOI：
10.1007/s00280-009-1112-8
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发表时间：
2010-05
影响因子：
3
通讯作者：
Davidson, Nancy E.
中科院分区：
文献类型：
--
作者：
Pledgie-Tracy, Allison;Billam, Madhavi;Hacker, Amy;Sobolewski, Michele D.;Woster, Patrick M.;Zhang, Zhe;Casero, Robert A.;Davidson, Nancy E.
多胺类似物作为单一药物以及与其他细胞毒性药物联合使用，已显示出对人类乳腺癌细胞系的显着活性。本研究评估了多胺类似物 N1, N11-双（乙基）去甲精胺 (BENSpm) 在四种人类乳腺癌细胞系和一种永生化细胞系中与六种标准化疗药物（5-氟尿嘧啶 (FU)、氟脱氧尿苷、顺式二胺氯铂 (II) (DDP)、紫杉醇、多西紫杉醇和长春瑞滨）协同作用的能力。非致瘤乳腺上皮细胞系。 BENSpm 与 5-FU 或紫杉醇联合使用，对人乳腺癌细胞系（MDA-MB-231 和 MCF-7）的细胞增殖具有协同抑制作用，而对非致瘤性 MCF-10A 细胞系则具有拮抗作用或效果较差。 120 小时伴随治疗或用 BENSpm 预处理 24 小时，然后再伴随治疗 96 小时，协同作用最高。由于许多多胺类似物和细胞毒性剂的细胞毒性作用被认为部分是通过诱导多胺分解代谢酶 SSAT 和 SMO 起作用，因此在用 BENSpm 和 5-FU 或紫杉醇处理的 MDA-MB-231 和 MCF-7 中评估了这些酶对协同反应的作用。与单独使用任一药物相比，BENSpm 与 5-FU 或紫杉醇的联合治疗导致两种细胞系中 SSAT mRNA 和活性的诱导，而 SMO mRNA 和活性仅在 MDA-MB-231 细胞中增加。 BENSpm/紫杉醇组合的诱导作用强于BENSpm/5-FU。此外，RNAi 研究表明，SSAT 和 SMO 在 MDA-MB-231 细胞对 BENSpm 和 5-FU 或紫杉醇治疗的反应中发挥着重要作用。在 MCF-7 细胞中，似乎只有 SSAT 参与了对这些治疗的反应。为了将联合研究从体外转化为体内，并为临床环境奠定基础，在用 MDA-MB-231 细胞生成的异种移植小鼠模型中评估了 BENSpm 单独使用以及与紫杉醇联合使用对肿瘤消退的体内治疗功效。腹腔内单独暴露于 BENSpm 或紫杉醇 4 周，并联合使用 4 周，可显着抑制肿瘤生长。这些发现有助于阐明协同药物反应所涉及的机制，并支持多胺类似物与化疗药物的组合，这可能用于治疗乳腺癌。
Polyamine analogues have demonstrated significant activity against human breast cancer cell lines as single agents as well as in combination with other cytotoxic drugs. This study evaluates the ability of a polyamine analogue N1, N11-bis(ethyl)norspermine (BENSpm) to synergize with six standard chemotherapeutic agents, 5-fluorouracil (FU), fluorodeoxyuridine, cis- diaminechloroplatinum(II) (DDP), paclitaxel, docetaxel, and vinorelbine, in four human breast cancer cell lines and one immortalized, non-tumorigenic mammary epithelial cell line. BENSpm exhibited synergistic inhibitory effect on cell proliferation in combination with 5-FU or paclitaxel in human breast cancer cell lines (MDA-MB-231 and MCF-7) and either antagonistic or less effective in the non-tumorigenic MCF-10A cell line. Synergism was highest with 120 hour concomitant treatment or pre-treatment with BENSpm for 24 hours followed by concomitant treatment for 96 additional hours. Since the cytotoxic effects of many polyamine analogues and cytotoxic agents are believed to act, in part, through induction of the polyamine catabolic enzymes SSAT and SMO, the role of these enzymes on synergistic response was evaluated in MDA-MB-231- and MCF-7-treated with BENSpm and 5-FU or paclitaxel. Combination treatments of BENSpm with 5-FU or paclitaxel resulted in induction of SSAT mRNA and activity in both cell lines compared to either drug alone, while SMO mRNA and activity were increased only in MDA-MB-231 cells. Induction was greater with BENSpm/paclitaxel combination than BENSpm/5-FU. Further, RNAi studies demonstrated that both SSAT and SMO play a significant role in the response of MDA-MB-231 cells to treatment with BENSpm and 5-FU or paclitaxel. In MCF-7 cells, only SSAT appears to be involved in the response to these treatments. In an effort to translate combination studies from in vitro to in vivo, and to form a basis for clinical setting, the in vivo therapeutic efficacy of BENSpm alone and in combination with paclitaxel on tumor regression was evaluated in xenograft mice models generated with MDA-MB-231 cells. Intraperitoneal exposure to BENSpm or taxol singly and in combination for 4 weeks resulted in significant inhibition in tumor growth These findings help elucidate the mechanisms involved in synergistic drug response and support combinations of polyamine analogues with chemotherapeutic agents which could potentially be used in the treatment of breast cancer.
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影响因子：
3.9
作者：
Camargo, SMR;Francescato, HDC;Bianchi, MLP
通讯作者：
Bianchi, MLP
影响因子：
3
作者：
CHANG, BK;BERGERON, RJ;LIBBY, PR
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作者：
BERGERON, RJ;NEIMS, AH;INGENO, MJ
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INGENO, MJ
影响因子：
4.7
作者：
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O'Brien, TG
影响因子：
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作者：
Allen, Wendy L.;McLean, Estelle G.;Johnston, Patrick G.
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Johnston, Patrick G.