Thomas T J, Thomas Thresia
Department of Medicine, Rutgers Robert Wood Johnson Medical School and Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 675 Hoes Lane West, KTL Room N102, Piscataway, NJ 08854, USA.
Retired from Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School and Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ 08854, USA.
Med Sci (Basel). 2018 Mar 13;6(1):24. doi: 10.3390/medsci6010024.
Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine ¹-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents.
与相邻正常组织相比，乳腺肿瘤中的多胺水平升高。女性性激素雌激素与乳腺癌的发生和发展有关。雌激素刺激而抗雌激素抑制多胺生物合成酶鸟氨酸脱羧酶（ODC）的表达。使用几种双（乙基）精胺类似物，我们发现这些类似物在培养中抑制雌激素受体阳性和雌激素受体阴性乳腺癌细胞的增殖。这些化合物在抑制细胞生长的功效方面存在构效关系。这些化合物抑制ODC的活性，而在MCF-7细胞中，双（乙基）去甲精胺使分解代谢酶亚精胺/精胺N1-乙酰基转移酶（SSAT）的活性增加了6倍。在乳腺癌转基因小鼠模型中，双（乙基）去甲精胺减少了自发性乳腺肿瘤的形成和生长。最近的研究表明，多胺分解代谢酶SSAT和精胺氧化酶（SMO）的诱导在多胺类似物及其与化疗药物如5-氟尿嘧啶（5-FU）和紫杉醇联合使用的抗增殖和凋亡作用中起关键作用。因此，多胺分解代谢酶可能是在将多胺类似物与其他治疗药物联合使用时重要的治疗靶点和敏感性标志物。
