The potential role of potent prolactin antagonists as chemotherapeutics for human cancers: An evaluation of select prolactin antagonists in human breast cancer cells.

摘要

Prolactin stimulates growth and lactation in mammary epithelial cells. Recent evidence shows most human breast tumors produce prolactin and express prolactin receptors, suggesting a local autocrine/paracrine system. Existing prolactin antagonists (G129R human prolactin) block prolactin receptor binding sites, interrupting the lactogenic autocrine system and slow human breast tumor cell growth. Unfortunately, the retention of substantial agonist activity renders these antagonists ineffective in investigating the role of prolactin in vivo.; We have designed a new and effective category of prolactin receptor antagonist. A lead compound, Delta41--52 human prolactin, has 12 deleted residues and retains 100-fold less agonist activity than earlier compounds. The Ohio State University has sought patent protection for the unique design of this new class of prolactin antagonists.; The work presented in this dissertation tests and compared the activity of Delta41--52 with wild-type and G129R human prolactins using standard bioassays. These studies have shown that prolactin acted not as a mitogen in human breast cancer cells as previously thought, but functioned as a survival factor. Using techniques, including microarrays, morphology and caspace assays, I have shown Delta41--52 human prolactin induced apoptosis in cell lines from both a human breast tumor (T47D) and a murine lymphoma (FDC-P1). In both cell lines, Delta41--52 was more effective than G129R human prolactin in decreasing the survival of cells in vitro.