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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gonadotropin-releasing hormone allalogue conjulugates with strong selective antitumor activity
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Gonadotropin-releasing hormone allalogue conjulugates with strong selective antitumor activity

机译：促性腺激素释放激素类似物具有很强的选择性抗肿瘤活性

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摘要

Conjugation of gonadotropin-releasing hormone (GnRH) analogues GnRH-III, MI-l544, and MI-1892 through lysyl side chains and a tetrapeptidc spacer, Gly-Phe- Leu-Gly (X) to a copolymer, poly(N-vinylpyrrolidone-co-maleic acid) (P) caused increased antiproliferative activity toward MCF-7 and MDA-MB-231 breast, PC3 and LNCaP prostate, and Ishikawa endometrial cancer cell lines in culture and against tumor development by xenografts of the breast Cancer cells in immunodeficient mice. MCF-7 cells treated witb P-X-l544 and P-X-l892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoPtotic bodies, bleb formation, and DNA fragmentation. Conjugates, but not free peptides, inhibited cdc25 phosphatase and caused accumulation of Ishikawa and PC3 cells in the G2/M phase of the cell cycle after 24 h at Iower doses and in the Gl and G2 phases after 48 h. Since P-X-peptides appear to be internalized, the increased cytotoxicity of the conjugates is attributed to protection of peptides from proteolysis, enhanced interaction of the peptides with the GnRH receptors, and/or internalization of P-X-peptide receptor complexes so that P can exert toxic effects inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of f PX-Peptides compared with free peptides for direct antipro liferative effects on the cancer cells but not for interactions in the pituitary indicates the therapheutic potential of the conjugates.
机译：促性腺激素释放激素（GnRH）类似物GnRH-III，MI-1544和MI-1892通过赖氨酰侧链和四肽间隔基Gly-Phe-Leu-Gly（X）与共聚物聚（N-乙烯基吡咯烷酮）偶联-顺-马来酸）（P）在培养中对MCF-7和MDA-MB-231乳腺癌，PC3和LNCaP前列腺癌以及Ishikawa子宫内膜癌细胞系的抗增殖活性增强，并抵抗乳腺癌细胞异种移植引起的肿瘤发展免疫缺陷小鼠。用P-X-1544和P-X-1892处理的​​MCF-7细胞显示出凋亡的特征性信号，包括细胞质中的液泡，聚集，无凋亡小体，气泡形成和DNA片段化。偶联物而非游离肽抑制cdc25磷酸酶并导致石川和PC3细胞在Iower剂量下24小时后在细胞周期的G2 / M期以及在48小时后在G1和G2期积聚。由于PX肽似乎被内在化，因此缀合物的细胞毒性增加归因于保护肽免受蛋白水解作用，肽与GnRH受体相互作用增强和/或PX肽受体复合物内在化，从而P可以发挥毒性作用。可能是通过抑制参与细胞周期的酶而产生的。与游离肽相比，f PX肽对癌细胞具有直接的抗增殖作用，但对垂体中的相互作用则没有特异性，这表明结合物的治疗潜力。

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