The effects of organ resection on rat urinary bladder carcinogenesis

Abstract

The effect of unilateral nephrectomy, orchiectomy or partial hepatectomy on the growth of chemically induced rat bladder tumors was investigated. Male F344 rats were treated with 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 5 weeks, and surgical resection of one of these organs was performed 2 weeks after the completion of BBN administration. Histological evaluation of the bladder 24 weeks after the start of the experiment revealed that unilateral nephrectomy and orchiectomy significantly increased the numbers of preneoplastic and neoplastic lesions as compared with the corresponding sham-operated groups. Partial hepatectomy also enhanced tumor growth, although not significantly. Immunohistochemical studies examining the effect of organ resection on normal bladder urothelium showed that BrdU immunostaining of urothelial cells significantly increased 7 days after unilateral nephrectomy or orchiectomy, while BrdU incorporation was minimum after partial hepatectomy or sham operation. C-met expression in the bladder urothelium was evident following unilateral nephrectomy or partial hepatectomy, while increased immunoreactivity of androgen receptor was noted following unilateral orchiectomy. Further study is needed to determine the exact mechanism of the bladder tumor growth-enhancing effect associated with organ restriction.

The emerging role of the androgen receptor in bladder cancer

“…One study found that unilateral orchiectomy actually promoted BBN induced bladder carcinogenesis in male rats (Saikawa et al 2001). Although these data seem contradictory to previous reports, the study noted that AR protein expression was higher following unilateral orchiectomy (Saikawa et al 2001). Thus, it is possible that despite orchiectomy, increased AR levels could compensate for decreased testosterone levels.…”

Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

“…The half-life was about one week (3 to 13 days) and the time to maximum concentration was between 30 minutes to 4 hours [60]. The first phase I/II study revealed 43% (13 of 30 patients) had PSA declines of 50% or greater [59]. In another important phase I/II study, 140 men with CRPC received increasing doses of enzalutamide (30-600 mg) and more than half of the patients had PSA declines (greater than 50%) [60].…”

“…Enzalutamide is an oral AR signaling inhibitor that not only blocks androgen binding to AR, with a 5-8 fold higher affinity compared to bicalutamide, but also prevents AR nuclear translocation, DNA binding, and coactivator recruitment [59]. The half-life was about one week (3 to 13 days) and the time to maximum concentration was between 30 minutes to 4 hours [60].…”

“…However, a 5a-reductase inhibitor finasteride showed marginal inhibitory effects on bladder tumor development (58), suggesting that testosterone itself may be a potent promoter of bladder carcinogenesis. Unilateral orchiectomy also led to a significantly higher incidence of bladder cancer, possibly because of a transient increase in the level of testosterone produced from the contralateral testis (59). In female animals, administration of testosterone with or without castration (bilateral ovariectomy) increased the bladder tumor incidence (57).…”

Lack of Influence of Testicular Castration or Sialoadenectomy on Sodium <i>L</i>-Ascorbate Promotion of Urinary Bladder Carcinogenesis in Male F344 Rats

“…In fact, testicular castration (TC) can decrease BBN-induced bladder carcinogenesis 8,9 with a reduction in the CYP4B1 level resp on sible fo r mu tagenic activation of bladder carcinogens 10 . However, when TC applied after BBNinitiation TC enhances both BrdU-incorporation into the urothelium and development of preneoplastic and/or neoplastic lesions 11 .…”