Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals.
Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals.
复制标题
与细胞毒性自由基相关的 LH-RH 类似物抑制大鼠实验性前列腺癌的生长。
DOI：
10.1002/pros.2990230209
复制
发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Nagy,A
中科院分区：
文献类型：
--
作者：
Pinski,J;Schally,AV;Yano,T;Szepeshazi,K;Halmos,G;Groot,K;Comaru-Schally,AM;Radulovic,S;Nagy,A
在携带Dunning R-3327 H前列腺腺癌的Copenhagen-Fisher Fl大鼠中评价了通过将蒽醌或甲氨蝶呤与载体LH-RH激动剂[D-Lys 6]LH-RH连接产生的杂合细胞毒性LH-RH类似物的作用。两种细胞毒性LH-RH类似物T-98 [与戊二酰-2-（羟甲基）蒽醌（G-HMAQ）偶联的（D-Lys 6）LH-RH]和AJ-04 [与甲氨蝶呤（MTX）连接的（D-Lys 6）LH-RH]、载体[D-Lys 6] LH-RH或游离细胞毒性化合物MTX和G-HMAQ从Alzet渗透微型泵给药7-8周。细胞毒性LH-RH类似物比载体肽引起更大的肿瘤生长抑制，而蒽醌或甲氨蝶呤单独以等摩尔剂量给药无效。载体和细胞毒性类似物对雄激素敏感器官（睾丸、腹侧前列腺和精囊）的抑制作用明显，表明后者在抑制垂体-性腺轴方面具有完全的生殖活性。还评价了组织学变化。在用AJ-04、T-98、[D-Lys 6]LH-RH或去势处理的肿瘤中，有丝分裂抑制和细胞凋亡频率高于对照组。血清激素水平降低载体肽和细胞毒性类似物，LH被大幅抑制，睾酮检测不到。这些结果和其他发现表明，含有细胞毒性自由基蒽醌或甲氨蝶呤的LH-RH类似物在体内给药后保留其激素活性，并可有效抑制肿瘤生长。需要对这类新化合物进行广泛的进一步研究，但细胞毒性LH-RH类似物与具有LH-RH受体的肿瘤（如前列腺癌）的明显结合可以大大降低化疗药物的外周毒性。这种基于靶向化疗的方法可能对晚期前列腺癌的管理具有实际的治疗意义，晚期前列腺癌最终在姑息性激素治疗后复发。© 1993 Wiley利斯公司
The effects of hybrid cytotoxic LH‐RH analogs, produced by linking anthraquinone or methotrexate to carrier LH‐RH agonist [D‐Lys6]LH‐RH, were evaluated in Copenhagen‐Fisher Fl rats bearing Dunning R‐3327H prostate adenocarcinoma. The two cytotoxic LH‐RH analogs T‐98 [(D‐Lys6)LH‐RH coupled to glutaryl‐2‐(hydroxymethyl)anthraquinone (G‐HMAQ)], and AJ‐04 [(D‐Lys6)LH‐RH linked to methotrexate (MTX)], carrier [D‐Lys6]LH‐RH, or the free cytotoxic compounds MTX and G‐HMAQ were administered from Alzet Osmotic minipumps for 7–8 weeks. The cytotoxic LH‐RH analogs caused somewhat greater tumor growth inhibition than the carrier peptide, while anthraquinone or methotrexate alone, administered in equimolar doses, were ineffective. The inhibition of androgen sensitive organs (testes, ventral prostates, and seminal vesicles) was pronounced with both carrier and cytotoxic analogs, showing the latter to be fully hormonally active in suppressing the pituitary‐gonadal axis. Histological changes were also evaluated. The inhibition of mitosis and the frequency of apoptosis were higher in tumors treated with AJ‐04, T‐98, [D‐Lys6]LH‐RH, or by castration than in those of controls. Serum hormone levels were lowered by both carrier peptide and cytotoxic analogs, LH being substantially depressed, and testosterone not detectable. These results and other findings indicate that LH‐RH analogs containing cytotoxic radicals anthraquinone or methotrexate retain their hormonal activity after administration in vivo, and can effectively inhibit tumor growth. Extensive further studies are required on this new class of compounds, but apparent binding of cytotoxic LH‐RH analogs to tumors such as prostate cancer, which have receptors for LH‐RH, could greatly reduce peripheral toxicity of chemotherapeutic agents. This approach, based on targeted chemotherapy, might be of practical therapeutic importance for the management of advanced prostate cancers, which eventually relapse after palliative hormonal therapy. © 1993 Wiley‐Liss, Inc.