Emons G, Gründker C, Günthert A R, Westphalen S, Kavanagh J, Verschraegen C
Department of Obstetrics and Gynecology, Georg-August-Universitaet, Robert-Koch-Strasse 40, D-37075 Goettingen, Germany.
Endocr Relat Cancer. 2003 Jun;10(2):291-9. doi: 10.1677/erc.0.0100291.
Approximately 80% of human ovarian and endometrial cancers and 50% of breast cancers express GnRH and its receptor as part of an autocrine regulatory system. After binding of its ligand the tumor GnRH receptor couples to G-protein alphai and activates a variety of intracellular signaling mechanisms. (1) Through activation of a protein tyrosine phosphatase, autophosphorylation of growth factor receptors is reverted leading to an inhibition of mitogenic signaling and reduced cell proliferation. (2) Through activation of nuclear factor kappa B antiapoptotic mechanisms are induced protecting tumor cells from apoptosis induced, for example, by doxorubicin. (3) Through activation of the Jun kinase pathway AP-1 is induced, leading to cell cycle arrest in the G0/G1 phase. It seems reasonable to speculate that this system enables the tumor cell to reduce proliferation and to activate repair mechanisms while being protected simultaneously from apoptosis. Interestingly, GnRH antagonists show the same activity in this system as agonists, indicating that the dichotomy GnRH agonist-GnRH antagonist defined in the pituitary gonadotrope is not valid for the tumor GnRH system. Recently, a second type of GnRH receptor, specific for GnRH-II, has been identified in ovarian and endometrial cancers, which transmits significantly stronger antiproliferative effects than the GnRH-I receptor. GnRH antagonists have agonistic effects on this type II receptor. In animal models of human cancers, GnRH antagonists had stronger antitumor effects than GnRH agonists. Therefore, we performed a phase II clinical trial with the GnRH antagonist, cetrorelix (10 mg/day), in patients with ovarian or mullerian carcinoma refractory to platinum chemotherapy. Of 17 evaluable patients treated with cetrorelix, 3 obtained a partial remission (18%) which lasted for 2 to 6 months. Furthermore, 6 patients experienced disease stabilization (35%) for up to 1 year. In this very refractory patient population (median number of prior chemotherapies = 3) these results are quite remarkable when compared with palliative chemotherapy. In addition, cytotoxic GnRH analogs have been developed, where for example doxorubicin was covalently coupled to GnRH analogs. These compounds have superior antitumor effects in cancers expressing GnRH receptors as compared with native doxorubicin and allow for a targeted cytotoxic chemotherapy of gynecologic and breast cancers.
大约80%的人类卵巢癌和子宫内膜癌以及50%的乳腺癌表达促性腺激素释放激素（GnRH）及其受体，作为自分泌调节系统的一部分。其配体结合后，肿瘤GnRH受体与G蛋白αi偶联并激活多种细胞内信号传导机制。（1）通过激活蛋白酪氨酸磷酸酶，生长因子受体的自磷酸化被逆转，导致有丝分裂信号传导受到抑制，细胞增殖减少。（2）通过激活核因子κB，诱导抗凋亡机制，保护肿瘤细胞免受例如阿霉素诱导的凋亡。（3）通过激活Jun激酶途径，诱导激活蛋白-1（AP-1），导致细胞周期停滞在G0/G1期。推测该系统能使肿瘤细胞减少增殖并激活修复机制，同时保护其免受凋亡，似乎是合理的。有趣的是，GnRH拮抗剂在该系统中显示出与激动剂相同的活性，这表明在垂体促性腺细胞中定义的GnRH激动剂 - GnRH拮抗剂二分法对肿瘤GnRH系统无效。最近，在卵巢癌和子宫内膜癌中发现了第二种类型的GnRH受体，它对GnRH-II具有特异性，其传递的抗增殖作用比GnRH-I受体显著更强。GnRH拮抗剂对这种II型受体具有激动作用。在人类癌症的动物模型中，GnRH拮抗剂的抗肿瘤作用比GnRH激动剂更强。因此，我们对铂类化疗难治的卵巢癌或苗勒管癌患者进行了一项使用GnRH拮抗剂西曲瑞克（10毫克/天）的II期临床试验。在17例接受西曲瑞克治疗的可评估患者中，3例获得部分缓解（18%），缓解持续2至6个月。此外，6例患者病情稳定（35%）长达1年。在这个非常难治的患者群体中（既往化疗的中位数次数 = 3），与姑息化疗相比，这些结果相当显著。此外，还开发了细胞毒性GnRH类似物，例如阿霉素与GnRH类似物共价偶联。与天然阿霉素相比，这些化合物在表达GnRH受体的癌症中具有更强的抗肿瘤作用，并允许对妇科癌症和乳腺癌进行靶向细胞毒性化疗。
