The effects of BCG-lytic peptide conjugates on ovarian function in ewes

生殖组织癌是生物医学研究的主要问题，前列腺癌和乳腺癌分别是男性和女性最常见的癌症形式。卵巢癌仍然是北美妇女的主要妇科死亡原因。由于传统的癌症治疗已被证明不太理想，对更具选择性的治疗类型的探索导致了结合裂解肽的发展。结合的裂解肽由连接到促性腺激素片段的小的细胞破坏多肽组成，使它们能够靶向特定表达促性腺激素/绒毛膜促性腺激素(LH/CG)受体的癌症组织。用结合在CG分子片段上的裂解肽来靶向乳腺癌、前列腺癌和卵巢癌的一个明显的优势是，生殖组织和生殖组织癌症比全身其他组织表达更多的黄体生成素/CG受体。在小鼠身上，结合的裂解肽已经能够有效地摧毁癌细胞，减轻肿瘤负担，同时据报道，对健康器官的损害很小。然而，关于它们在排卵周期的不同阶段对正常卵巢结构的影响的信息缺乏。因此，本研究的目的是确定其中一种结合物Phor21-？CG(ALA)及其对映体Cg(ALA)-Phor21对内源性黄体生成素控制的卵巢突起的影响。作为初步方法，超声图像和生殖激素测量将用于实时评估有腔卵泡发育、排卵和黄体结构，并以绵羊为实验模型。据预测，促黄体激素受体在排卵前卵泡和黄体(CL)上的密集表达将为结合物提供合适的靶点，从而扰乱正常的卵巢功能。随着这些药物走向人类临床试验，在大型哺乳动物动物模型中，有证据表明它们对卵巢动态过程的影响是非常重要的。这可能对Phor21-？Cg(Ala)和？Cg(Ala)-Phor21作为治疗剂的使用有重要影响，或在未来潜在的避孕作用或作为研究工具。

Reproductive tissue cancers are of primary concern for biomedical research, with prostate and breast cancers being the most frequent forms seen in men and women, respectively. Ovarian cancers continue to be a leading gynaecological cause of death in North American women. As conventional cancer therapy has proven less than ideal, the search for a more selective type of treatment has lead to the development of conjugated lytic peptides. The conjugated lytic peptides consist of small, cell-disrupting peptides linked to the fragments of gonadotropin hormones, allowing them to target cancer tissue specifically expressing the lutropin/choriogonadotropin (LH/CG) receptor. A distinct advantage of targeting breast, prostate and ovarian cancers with the lytic peptide conjugated to the fragment of CG molecule is that reproductive tissues and reproductive tissue cancers express the LH/CG receptor in much greater abundance than other tissues throughout the body. In mice, conjugated lytic peptides have been able to effectively destroy cancer cells and reduce the tumour burden while reportedly causing little damage to healthy organs. However, there is a lack of information on their effects on normal ovarian structures during different stages of the ovulatory cycle. Thus, the aim of the proposed studies is to determine the effects of one such conjugate, Phor21-ßCG(ala) and its enantiomer ßCG(ala)-Phor21, on the ovarian processes governed by endogenous LH. As an initial approach, ultrasound images and reproductive hormone measurements will be used for real-time assessment of antral follicular development, ovulation and luteal structures, using sheep as an experimental model. It is predicted that the dense expression of LH receptors on the preovulatory follicle and corpus luteum (CL) will present an appropriate target the conjugates, and disrupt normal ovarian function. As these drugs move towards human clinical trials, it is of great importance to have evidence indicating their effects on the dynamic processes in the ovaries, in a large mammalian animal model. This may have important bearing on the use of Phor21-ßCG(ala) and ßCG(ala)-Phor21 as therapeutic agents, or potentially in a contraceptive role or as a research tool in the future.