Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: Current options and emerging strategies.
Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: Current options and emerging strategies.
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DOI：
10.1016/j.ctrv.2012.12.003
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发表时间：
2013-10
影响因子：
11.8
通讯作者：
P. Limonta;M. Manea
中科院分区：
文献类型：
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作者：
P. Limonta;M. Manea
前列腺癌早期依赖雄激素，去雄激素治疗是最有效的一线治疗方法。然而，在最初的缓解之后，前列腺癌发展到耐去势前列腺癌(CRPC)阶段，恶性程度增加，对传统化疗耐药。促性腺激素释放激素受体(GnRH-Rs)是治疗激素依赖型前列腺癌最有效的分子靶点。GnRH激动剂(通过GnRH-Rs脱敏)抑制垂体-睾丸轴，因此，代表前列腺癌患者的治疗选择。GnRH-R在前列腺癌中也有表达，甚至当肿瘤达到CRPC阶段时也是如此，并具有抗肿瘤活性，支持它们可能是GnRH类似物治疗策略的分子靶点的观点。除了GnRH激动剂和拮抗剂外，基于GnRH的生物结合物(细胞毒性GnRH生物结合物、GnRH偶联裂解肽和GnRH毒素生物结合物)已被开发出来，目前正在进行深入的研究；其中一些已进入临床试验。这些治疗的优势是将细胞毒剂特异性地输送到癌细胞。有趣的是，这种多肽的其他异构体已经被鉴定出来。其中一个是GnRH-III，它是从七鳃鳗中分离出来的。GnRH-III与癌细胞中的GnRH-R特异性结合，发挥抗增殖作用；另一方面，其在脑垂体水平的内分泌作用不明显，支持其选择性抗肿瘤活性。基于这些观察，最近已经合成了不同的细胞毒性GnRH-III生物偶联物；初步的体外研究表明，这些化合物可能是前列腺癌的一种新的有希望的治疗策略。
Prostate cancer is androgen-dependent in its early stages and androgen deprivation therapy represents the most effective first-line therapeutic approach. However, after an initial remission, prostate cancer progresses towards the castration resistant prostate cancer (CRPC) stage, with increased malignancy and resistance to conventional chemotherapy. Pituitary gonadotropin-releasing hormone receptors (GnRH-Rs) represent the most effective molecular target for the treatment of steroid-dependent prostate cancer. GnRH agonists (through GnRH-Rs desensitization) suppress the pituitary–testicular axis and, therefore, represent the treatment of choice for prostate cancer patients. GnRH-Rs are also expressed in prostate cancer, even when the tumor has reached the CRPC stage, and are endowed with antitumor activity, supporting the notion that they might represent a molecular target for GnRH analog-based therapeutic strategies. In addition to GnRH agonists and antagonists, GnRH-based bioconjugates (cytotoxic GnRH bioconjugates, GnRH-conjugated lytic peptides and GnRH-toxin bioconjugates) have been developed and are now undergoing intensive investigations; some of them (i.e., AN-152, Dox-[d-Lys6]-GnRH) have entered clinical trials. The advantage of these treatments is the specific delivery of cytotoxic agents to cancer cells. Interestingly, other isoforms of the peptide have been identified. One of them is GnRH-III, which was isolated from sea lamprey. GnRH-III specifically binds to GnRH-Rs in cancer cells and exerts antiproliferative effects; on the other hand, its endocrine effects at pituitary level are insignificant, supporting its selective antitumor activity. Based on these observations, different cytotoxic GnRH-III bioconjugates have recently been synthesized; preliminary in vitro studies suggest that these compounds might represent a new promising treatment strategy for prostate cancer.