Generation of Transgenic Animals Producing Ezymatically Active Prostate- Specific Antigen (PSA) in Normal and Malignant Prostate Tissue

摘要

Prostate-specific antigen (PSA) is used extensively as a serum marker to screen for prostate cancer and is also used as a surrogate marker to assess response to therapy for prostate cancer. The physiologic role of PSA in normal prostate biology is uncertain but the protein appears to play a role in reproduction by enhancing sperm mobility. PSA is a serine protease with chymotrypsin-like specificity. PSA, through it proteolytic activity, may plan an important role in prostate cancer progression, invasion, angiogenesis, and/or metastasis. To date, no lab has successfully produced a mammalian cell line that makes large amounts of enzymatically active PSA. This inactivity appears to be due to lack or, or incomplete processing of, Pro-PSA to the active form, presumably due to the absence of the necessary processing protease. Currently available prostate cancer cell lines and mouse models producing enzymatically inactive PSA are not useful for developing these prodrug therapies or for understanding the role of PSA in the biology of prostate cancer. we have generated a modified PSA gene that was used to generate cell lines that produce much higher levels of total PSA and most of this PSA is enzymatically active. This PSA gene was used to generate mice that produce PSA in their prostates. These mice can be used to study role of PSA in biology of prostate cancer and to test PSA-activated prodrug therapies.