title: 5α-reductase inhibition suppresses testosterone-induced initial regrowth of regressed xenograft prostate tumors in animal models.
abstract: Androgen deprivation therapy (ADT) is the standard treatment for patients with prostate-specific antigen progression after treatment for localized prostate cancer. An alternative to continuous ADT is intermittent ADT (IADT), which allows recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor. IADT offers patients a reduction in side effects associated with ADT, improved quality of life, and reduced cost with no difference in overall survival. Our previous studies showed that IADT coupled with 5α-reductase inhibitor (5ARI), which blocks testosterone conversion to DHT could prolong survival of animals bearing androgen-sensitive prostate tumors when off-cycle duration was fixed. To further investigate this clinically relevant observation, we measured the time course of testosterone-induced regrowth of regressed LuCaP35 and LNCaP xenograft tumors in the presence or absence of a 5ARI. 5α-Reductase inhibitors suppressed the initial regrowth of regressed prostate tumors. However, tumors resumed growth and were no longer responsive to 5α-reductase inhibition several days after testosterone replacement. This finding was substantiated by bromodeoxyuridine and Ki67 staining of LuCaP35 tumors, which showed inhibition of prostate tumor cell proliferation by 5ARI on day 2, but not day 14, after testosterone replacement. 5α-Reductase inhibitors also suppressed testosterone-stimulated proliferation of LNCaP cells precultured in androgen-free media, suggesting that blocking testosterone conversion to DHT can inhibit prostate tumor cell proliferation via an intracrine mechanism. These results suggest that short off-cycle coupled with 5α-reductase inhibition could maximize suppression of prostate tumor growth and, thus, improve potential survival benefit achieved in combination with IADT.
authors.affiliation: Department of Urology, Hillman Cancer Centre, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
authors.forename: Khalid Z
authors.initials: KZ
authors.lastname: Masoodi
authors.forename: Raquel
authors.initials: R
authors.lastname: Ramos Garcia
authors.forename: Laura E
authors.initials: LE
authors.lastname: Pascal
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Hei M
authors.initials: HM
authors.lastname: Ma
authors.forename: Katherine
authors.initials: K
authors.lastname: O'Malley
authors.forename: Kurtis
authors.initials: K
authors.lastname: Eisermann
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Shevrin
authors.forename: Holly M
authors.initials: HM
authors.lastname: Nguyen
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Joel B
authors.initials: JB
authors.lastname: Nelson
authors.forename: Rahul A
authors.initials: RA
authors.lastname: Parikh
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wang
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068538:Dutasteride; D018120:Finasteride / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D000077289:Letrozole; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000009:adverse effects*; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D009570:Nitriles; D014230:Triazoles; D013739:Testosterone; D018120:Finasteride; D000077289:Letrozole; D000068538:Dutasteride