Polyamine depletion therapy in prostate cancer
Polyamine depletion therapy in prostate cancer
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DOI：
10.1038/sj.pcan.4500420
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发表时间：
2000-01-01
影响因子：
4.8
通讯作者：
Brawer, MK
中科院分区：
文献类型：
--
作者：
Devens, BH;Weeks, RS;Brawer, MK
前列腺是体内多胺含量最高的腺体之一，前列腺癌的多胺水平甚至更高。这些由前列腺上皮合成的普遍存在的分子参与许多生化过程，包括细胞增殖、细胞周期调节和蛋白质合成。这些特性使多胺成为治疗癌症等细胞过度增殖疾病的潜在目标。然而，通过抑制多胺合成来限制肿瘤生长的尝试并不是很成功，因为细胞具有从血流中吸收多胺的能力。我们在这里报告利用多胺消耗的研究，通过结合使用 DFMO（α-二氟甲基鸟氨酸）（一种鸟氨酸脱羧酶抑制剂，多胺合成途径中的限速酶）和 ORI 1202（一种多胺转运到细胞内的新型抑制剂）来阻断多胺合成。即使存在过量的细胞外多胺，这种细胞抑制组合也能显着减缓组织培养物中人肿瘤细胞系 PC-3 的生长，EC50 在 muM 范围内。其他前列腺细胞系也受到类似的生长抑制，包括LNCaP.FGC和DU145。这种化合物的组合也显着减缓了作为裸鼠异种移植物的PC-3肿瘤细胞系的生长。肿瘤中的多胺水平比对照肿瘤水平降低。这种联合疗法可以为前列腺肿瘤提供有效且潜在无毒的疗法。
The prostate gland has among the highest level of polyamines in the body and prostate carcinomas have even greater elevated polyamine levels. These ubiquitous molecules synthesized by prostate epithelium are involved in many biochemical processes including cellular proliferation, cell cycle regulation, and protein synthesis. These properties have made polyamines a potential target for therapeutic intervention in diseases of excessive cell proliferation such as cancer. However, attempts to limit tumor growth by inhibition of polyamine synthesis have not been very successful since cells have the capacity to take up polyamines from the bloodstream. We report here studies utilizing polyamine depletion by means of a combination of blockade of polyamine synthesis with DFMO (alpha -difluoromethylornithine), an inhibitor of ornithine decarboxylase, the rate limiting enzyme in the polyamine synthetic pathway, and ORI 1202, a novel inhibitor of polyamine transport into the cell. This cytostatic combination, even in the presence of excess extracellular polyamines, significantly slowed the growth of the human tumor cell line PC-3 grown in tissue culture with an EC50 in the muM range. Other prostate cell lines were similarly growth inhibited including LNCaP.FGC and DU145. Growth of the PC-3 tumor cell line as a xenograft in nude mice was also slowed significantly by this combination of compounds. Polyamine levels in the tumor were lowered from control tumor levels. This combination therapy could provide an effective and potentially non-toxic therapy for prostate tumors.