Lipophilic Lysine-Spermine Conjugates Are Potent Polyamine Transport Inhibitors for Use in Combination with a Polyamine Biosynthesis Inhibitor
Lipophilic Lysine-Spermine Conjugates Are Potent Polyamine Transport Inhibitors for Use in Combination with a Polyamine Biosynthesis Inhibitor
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DOI：
10.1021/jm801580w
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发表时间：
2009-04-09
影响因子：
7.3
通讯作者：
O'Brien, Thomas G.
中科院分区：
文献类型：
--
作者：
Burns, Mark R.;Graminski, Gerard F.;O'Brien, Thomas G.
癌细胞可以通过从外部来源输入多胺来克服多胺生物合成抑制剂完全耗尽其内部多胺的能力。本文讨论了一组亲脂性多胺类似物的发展，有效地抑制细胞多胺摄取系统，并大大提高多胺消耗的有效性时，与DFMO，一个研究充分的多胺生物合成抑制剂组合使用。将长度优化的C-16亲脂性取代基连接到早期先导化合物D-Lys-Spm（5）的e-氮原子上，产生了类似物D-Lys（C（16）酰基）-Spm（11），其对多种培养的癌细胞类型（包括乳腺癌）具有几个数量级更有效的细胞生长抑制作用。（MDA-MB-231）、前列腺（PC-3）、黑素瘤（A375）和卵巢（SK-0 V-3）等。这些结果进行了讨论的背景下，可能的膜催化的相互作用与细胞外多胺运输装置。由此产生的新型靶向细胞多胺代谢的双药联合治疗在皮肤癌的转基因鸟氨酸脱羧酶（ODC）小鼠模型中显示出对皮肤鳞状细胞癌（SCC）的卓越疗效。大多数（88%）大型侵袭性SCC对该联合治疗表现出完全或接近完全缓解，而对每种药物单独治疗的反应较差。有效的多胺转运抑制剂的可用性允许，第一次，为一个真实的测试的假设，饥饿细胞的多胺将导致客观的临床反应。
Cancer cells can overcome the ability of polyamine biosynthesis inhibitors to completely deplete their internal polyamines by the importation of polyamines from external sources. This paper discusses the development of a group of lipophilic polyamine analogues that potently inhibit the cellular polyamine uptake system and greatly increase the effectiveness of polyamine depletion when used in combination with DFMO, a well-studied polyamine biosynthesis inhibitor. The attachment of a length-optimized C-16 lipophilic substituent to the e-nitrogen atom of an earlier lead compound, D-Lys-Spm (5), has produced an analogue, D-Lys(C(16)acyl)-Spm (11) with several orders of magnitude more potent cell growth inhibition on a variety of cultured cancer cell types including breast (MDA-MB-231), prostate (PC-3), melanoma (A375), and ovarian (SK-OV-3), among others. These results are discussed in the context of a possible membrane-catalyzed interaction with the extracellular polyamine transport apparatus. The resulting novel two-drug combination therapy targeting cellular polyamine metabolism has shown exceptional efficacy against cutaneous squamous cell carcinomas (SCC) in a transgenic ornithine decarboxylase (ODC) mouse model of skin cancer. A majority (88%) of large, aggressive SCCs exhibited complete or nearly complete remission to this combination therapy, whereas responses to each agent alone were poor. The availability of a potent polyamine transport inhibitor allows, for the first time, for a real test of the hypothesis that starving cells of polyamines will lead to objective clinical response.