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

生殖组织癌是加拿大男性和女性关注的主要问题。乳腺癌和前列腺癌在新增临床病例中仅次于肺癌。为了提高与生殖癌症有关的存活率，已经动用了数百万加元和无数资源。虽然原发性、局部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，这种情况30多年来没有改变。传统的癌症治疗（即放疗和化疗）与严重的不必要的全身效应和多重耐药性有关。这导致了新的靶向癌症治疗方法的发展，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体，携带裂解肽到表达恭维受体的细胞。目前正在研究的缀合物利用促性腺激素释放激素（GnRH）或黄体生成素（LH）受体。靶向这些受体的明显优势是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GnRH受体也在垂体前腺中密集表达，而LH受体在排卵前后的卵巢中也大量表达。到目前为止，还没有研究评估了缀合物对GnRH和lh介导的生殖过程的影响。随着这些药物走向人体临床试验，在大型动物模型中有证据表明它们对动态卵巢功能的影响将具有重要价值。因此，我们的主要目标是评估共轭裂解肽对母羊垂体功能和卵巢动力学的影响。研究结果确定了这些药物对生殖器官的影响，可能对它们在癌症治疗中的应用有重要影响，并可能在未来的避孕和溶黄体作用中发挥重要作用。

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.