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关注点，前列腺癌和乳腺癌分别是男性和女性中最常见的形式。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被证明不太理想，寻找一种更有选择性的治疗方法已经导致了共轭裂解肽的发展。结合的裂解肽由小的细胞破坏肽组成，与促性腺激素的片段相连，使它们能够靶向特异性表达lutropin/绒毛膜促性腺激素（LH/CG）受体的癌症组织。结合CG分子片段的裂解肽靶向乳腺癌、前列腺癌和卵巢癌的一个明显优势是，生殖组织和生殖组织癌表达的LH/CG受体比全身其他组织丰富得多。在小鼠中，结合的裂解肽能够有效地破坏癌细胞并减少肿瘤负担，同时据报道对健康器官几乎没有损害。然而，缺乏关于它们在排卵周期不同阶段对正常卵巢结构的影响的信息。因此，拟议研究的目的是确定一种这样的缀合物Phor21-ßCG（ala）及其对映体ßCG(ala)-Phor21对内源性LH控制的卵巢过程的影响。作为初步方法，超声图像和生殖激素测量将用于实时评估窦卵泡发育，排卵和黄体结构，以羊为实验模型。预计在排卵前卵泡和黄体（CL）上密集表达的LH受体将为偶联物提供合适的靶点，从而破坏卵巢正常功能。随着这些药物进入人体临床试验，在大型哺乳动物模型中，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-ßCG（ala）和ßCG(ala)-Phor21作为治疗剂，或潜在的避孕作用或未来的研究工具有重要影响。

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.