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

卡介苗-裂解肽缀合物对母羊卵巢功能的影响

• 批准号: 311647-2009
• 负责人: Bartlewski, Pawel
• 金额: $ 1.75万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=427811
• 关键词: effects; BCG; lytic; peptide; conjugates

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.

生殖组织癌症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最常见的癌症。卵巢癌仍然是北美妇女死亡的主要妇科原因。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缀合裂解肽的开发。结合的裂解肽由与促性腺激素片段连接的小的细胞破坏肽组成，使其能够靶向特异性表达促黄体激素/绒毛膜促性腺激素（LH/CG）受体的癌组织。用与CG分子片段缀合的裂解肽靶向乳腺癌、前列腺癌和卵巢癌的明显优点是生殖组织和生殖组织癌表达LH/CG受体的丰度比全身其他组织高得多。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造成的损害很小。然而，在排卵周期的不同阶段，它们对正常卵巢结构的影响缺乏信息。因此，所提出的研究的目的是确定一种这样的缀合物Phor 21-β CG（ala）及其对映体β CG（ala）-Phor 21对由内源性LH控制的卵巢过程的影响。作为一种初步的方法，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，使用绵羊作为实验模型。据预测，LH受体在排卵前卵泡和黄体（CL）上的密集表达将为缀合物提供合适的靶点，并破坏正常的卵巢功能。随着这些药物进入人体临床试验，在大型哺乳动物模型中获得表明其对卵巢动态过程影响的证据非常重要。这可能对Phor 21-β CG（ala）和β CG（ala）-Phor 21作为治疗剂、或潜在地作为避孕作用或作为未来的研究工具的用途具有重要意义。