The effects of a lytic peptide phor-21 conjugated to beta chorionic gonadotropin (ßCG) or GnRH on ovarian dynamics in ewes

裂解肽 phor-21 与 β 绒毛膜促性腺激素 (CG) 或 GnRH 结合对母羊卵巢动态的影响

• 批准号: 311647-2010
• 负责人: Bartlewski, Pawel
• 金额: $ 1.97万
• 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: 2010
• 资助国家: 加拿大
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=457080
• 关键词: effects; lytic; peptide; phor; 21

Reproductive tissue cancers represent a major concern for Canadian men and women. Breast and prostate cancers fall behind only lung cancer as the leading number of new clinical cases. Millions of Canadian dollars and countless resources have been utilized in an attempt to increase the survival rates associated with reproductive cancers. Although the survival rates of the primary, localized disease have increased by almost 100%, the prognosis for patients with distant, metastatic disease is still very poor and this has not changed for more than thirty years. Conventional cancer therapy (i.e., radiation and chemotherapy) is associated with severe unwanted systemic effects and multi-drug resistance. This led to the development of new, targeted cancer treatments that show the ability to eliminate both primary and advanced, or metastatic, tumours. This therapy utilizes peptide hormones or their receptor-binding fragments as molecular cytotoxic transporters carrying lytic peptides to cells expressing compliment receptors. The conjugates currently under investigation utilize gonadotropin releasing hormone (GnRH) or luteinizing-hormone (LH) receptors. The distinct advantage of targeting these receptors is that they are densely expressed on reproductive tissue tumors but negligible in other organs. However, high-affinity GnRH receptors are also densely expressed in the anterior pituitary gland and LH receptors are abundant in ovaries around ovulation. To date, no studies have evaluated the effects of the conjugates on GnRH- and LH-mediated reproductive processes. As these drugs move towards human clinical trials, it will be of great value to have evidence indicating their impact on the dynamic ovarian function in a large animal model. Therefore, our primary goal is to assess the effects of the conjugated lytic peptides on the pituitary function and ovarian dynamics in ewes. The results of the studies determining the effects of these drugs on the reproductive organs may have important bearing on their use in a cancer therapy and, potentially, in contraceptive and luteolytic roles in future.

生殖组织癌症是加拿大男女的一个主要关切。乳腺癌和前列腺癌仅次于肺癌，成为新临床病例的主要数量。数百万加拿大元和无数资源被用于提高生殖系统癌症患者的存活率。虽然原发性、局部性疾病的生存率几乎增加了100%，但远处转移性疾病患者的预后仍然很差，并且三十多年来没有改变。常规的癌症治疗（即，放射和化学疗法）与严重的不希望的全身效应和多药耐药性有关。这导致了新的靶向癌症治疗方法的开发，这些治疗方法显示出消除原发性和晚期或转移性肿瘤的能力。这种疗法利用肽激素或其受体结合片段作为分子细胞毒性转运蛋白，将裂解肽携带至表达补体受体的细胞。目前正在研究的缀合物利用促性腺激素释放激素（GnRH）或促黄体激素（LH）受体。靶向这些受体的独特优势在于它们在生殖组织肿瘤上密集表达，但在其他器官中可以忽略不计。然而，高亲和力GnRH受体也密集表达于垂体前叶，LH受体在排卵前后的卵巢中丰富。到目前为止，没有研究评估了结合物对GnRH和LH介导的生殖过程的影响。随着这些药物进入人体临床试验，在大型动物模型中获得表明其对动态卵巢功能影响的证据将具有重要价值。因此，我们的主要目标是评估缀合裂解肽对母羊垂体功能和卵巢动力学的影响。确定这些药物对生殖器官的影响的研究结果可能对它们在癌症治疗中的应用以及未来可能在避孕和黄体溶解作用中的应用具有重要意义。