Prolongation of off‐cycle interval by finasteride is not associated with survival improvement in intermittent androgen deprivation therapy in LNCaP tumor model

Wang, Yujuan; Gupta, Shubham; Hua, Vi N.; Ramos-Garcia, Raquel; Shevrin, Daniel H.; Jovanovic, Borko; Nelson, Joel B.; Wang, Zhou

doi:10.1002/pros.21046

Cited by 13 publications

(29 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tumors were measured weekly and volume was calculated by the modified ellipsoid formula: length ϫ width 2 ϫ 0.52 (34). For the castration group, transscrotal castration was performed under isoflurane anesthesia with proper aseptic and antiseptic technique as previously (28). Mice were initially randomized into 2 groups, testis-intact and castration, when xenograft tumors reached a volume of 200 mm 3.…”

Section: Treatment Protocol and Measurement Of Tumor Growthmentioning

confidence: 99%

“…Pellets were prepared as previously described (28). Briefly, approximately 7.5 mg testosterone (Sigma Chemical Co, St Louis, Missouri) was tightly packed into a silicone tube with an inner and outer diameter of 1.58 and 3.18 mm, respectively (Helix Medical, Carpenteria, California).…”

Section: Construction Of Testosterone Dutasteride and Finasteride Pmentioning

confidence: 99%

“…Our initial studies showed that addition of finasteride to the off-cycle increased survival over IADT alone in LNCaP xenografts when the off-cycle interval was fixed (13). Subsequent studies showed that finasteride doubled the off-cycle interval in IADT, when the off-cycle was terminated based on tumor volume (28). However, prolongation of the off-cycle in the presence of finasteride did not translate into a survival benefit (28).…”

mentioning

confidence: 95%

“…Subsequent studies showed that finasteride doubled the off-cycle interval in IADT, when the off-cycle was terminated based on tumor volume (28). However, prolongation of the off-cycle in the presence of finasteride did not translate into a survival benefit (28). Similarly, in a retrospective clinical study, Scholz et al (25) reported that use of finasteride during the off-cycle doubled its duration from a median of 15 months to a median of 31 months with no effect on prostate cancer progression to castration resistance, when off-cycle termination was based on serum PSA.…”

mentioning

confidence: 98%

“…IADT consists of multiple cycles of androgen suppression, termed on-cycle, where prostate tumors undergo regression, followed by a period of testosterone recovery and tumor regrowth, or off-cycle (18,26). Rising serum prostate-specific antigen (PSA) level is often used as an indication to restart ADT (27); however, there is currently no clearly defined guideline for timing of resuming ADT in these patients (28).…”

mentioning

confidence: 99%

See 4 more Smart Citations

5α-Reductase Inhibition Suppresses Testosterone-Induced Initial Regrowth of Regressed Xenograft Prostate Tumors in Animal Models

et al. 2013

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Treatment Protocol and Measurement Of Tumor Growthmentioning

confidence: 99%

Section: Construction Of Testosterone Dutasteride and Finasteride Pmentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 98%

mentioning

confidence: 99%

See 3 more Smart Citations

5α-Reductase Inhibition Suppresses Testosterone-Induced Initial Regrowth of Regressed Xenograft Prostate Tumors in Animal Models

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

Inhibition of 5α‐reductase enhances testosterone‐induced expression of U19/Eaf2 tumor suppressor during the regrowth of LNCaP xenograft tumor in nude mice

et al. 2010

Self Cite

View full text Add to dashboard Cite

BACKGROUND Intermittent androgen deprivation therapy (IADT) was developed to improve the quality of life and retard prostate cancer progression to castration resistance. IADT involves regrowth of the tumor during the off cycle upon testosterone recovery. Our previous studies showed that testosterone is more potent than dihydrotestosterone (DHT) in the induction of a subset of androgen-responsive genes during rat prostate regrowth. However, it is not clear if the same phenomenon would occur during androgen-induced regrowth of prostate tumors. Understanding the differences between testosterone and DHT in inducing androgen-responsive genes during prostate tumor regrowth may provide new insight for improving IADT. METHODS Nude mice bearing androgen-sensitive LNCaP xenograft were castrated and followed up for 7–10 days before being randomized into various androgen manipulations, consisting of continuous castration (C) or testosterone replacement (T) in the absence or presence of dutasteride (D), a 5α-reductase inhibitor that blocks the conversion of testosterone to DHT. Testes-intact animals in the absence or presence of D were used as controls. The expression of five androgen-responsive genes, including the tumor suppressor U19/Eaf2, was determined using real-time RT-PCR, 3 days after randomization. RESULTS In LNCaP tumors, the expression of U19/Eaf2 was higher in the T+D group as compared with T alone (2.87-fold, P < 0.05). In contrast, dutasteride treatment in testes-intact animals inhibited the expression of U19/Eaf2. CONCLUSIONS Inhibition of 5α-reductase during LNCaP tumor regrowth enhanced the expression of U19/Eaf2, an androgen-regulated tumor suppressor. This finding suggests that off cycle 5α-reductase inhibition may enhance the efficacy of IADT.

show abstract

Prostatakarzinom

Börgermann¹,

Chun²,

Bastian³

et al. 2014

Uroonkologie

View full text Add to dashboard Cite

Prolongation of off‐cycle interval by finasteride is not associated with survival improvement in intermittent androgen deprivation therapy in LNCaP tumor model

Cited by 13 publications

References 18 publications

5α-Reductase Inhibition Suppresses Testosterone-Induced Initial Regrowth of Regressed Xenograft Prostate Tumors in Animal Models

5α-Reductase Inhibition Suppresses Testosterone-Induced Initial Regrowth of Regressed Xenograft Prostate Tumors in Animal Models

Inhibition of 5α‐reductase enhances testosterone‐induced expression of U19/Eaf2 tumor suppressor during the regrowth of LNCaP xenograft tumor in nude mice

Prostatakarzinom

Contact Info

Product

Resources

About