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

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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.