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.

Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro

“…In our study, DHT decreased when progesterone was present but DHT increased in the absence of precursor progesterone. When LuCaP xenografts were treated with dutasteride there was an increase in testosterone while our in vitro study with 22RV1 cells a decrease was observed [40,41]. These differences can be attributed to the inherent differences between each cell line and how they uniquely adapt to treatment as well as how the tumor microenvironment in the in vivo models influences steroidogenesis.…”

Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules

“…Tumor tissue samples were fixed immediately after dissection in 10% formalin overnight, dehydrated in ethanol, cleared in xylene, and embedded in paraffin blocks, as previously described (26). Six micrometer-thick sections were prepared, mounted on positive charged slides (Fisher Biotech, Pittsburgh, PA), and air-dried overnight.…”

Improving intermittent androgen deprivation therapy: lessons learned from basic and translational research

“…We observed that finasteride or dutasteride caused an initial inhibition of regrowth and then the tumors resume growth at the same rate as that of the control group as measured by tumor volume ( Figure 2 ). The initial regrowth inhibition by 5 alpha-reductase inhibitor was confirmed by reduced Ki-67 staining and BrdU incorporation assay 53. Both assays showed a statistically significant inhibition (~10-fold) of proliferation index by 5 alpha-reductase inhibitors during the initial phase of regrowth, but not after prolonged exposure to testosterone.…”