Renal tumors in male rats following long-term administration of bazedoxifene, a tissue-selective estrogen receptor modulator.

Bazedoxifene acetate (BZA) is a selective estrogen receptor modulator that is approved in a number of countries for the prevention and/or treatment of osteoporosis in postmenopausal women. To assess carcinogenic potential, BZA was administered ad libitum in the diet to male and female rats for 2 years. The achieved mean dosages of BZA were approximately 1.31 to 56.9 mg/kg/day at dietary concentrations of 0.003% to 0.1%. BZA treatment resulted in a reduction and a delayed onset in total tumor burden in both male and female rats. Survival rates were enhanced due to decreased pituitary and mammary tumors and decreased body weight gain in BZA-treated animals compared with controls. In male rats only, an increase in renal tubular tumors was observed. The greater increase in tumor incidence in male rats given BZA was associated with the increased survival and increased time for development of late onset tumors. These findings are consistent with a non-genotoxic mechanism, unique to male rats, that involves test article-induced corticomedullary mineralization, renal tubular injury, and exacerbation of naturally occurring chronic progressive nephropathy in aged male rats that led to a sequela of proliferative changes and tumor formation.

Carcinogenicity and hormone studies with the tissue-selective estrogen receptor modulator bazadoxifene.

Bazedoxifene Acetate (BZA) is a selective estrogen receptor modulator (SERM) that is approved for the prevention and/or treatment of osteoporosis in postmenopausal women. To assess for carcinogenic potential, BZA was administered ad libitum in the diet to rats for 2 years. BZA caused an increase in benign ovarian tumors in female rats and decreased incidences of mammary tumors (females) and pituitary tumors (males and females). In addition, BZA provided a significant survival benefit at all dosages tested, which correlated with a significant reduction in pituitary and mammary gland tumors and decreased body weight gain (both genders). Additional studies were subsequently conducted in rats and monkeys to further explore the mechanisms likely responsible for the observed effects. Results from studies in hypophysectomized and chemically castrated female rats indicated that BZA did not directly stimulate formation of ovarian cysts, but an intact pituitary was required for cyst formation. Further, BZA increased estradiol concentrations in rats and monkeys. In monkeys, BZA increased concentrations of luteinizing hormone (LH) after onset of treatment and prohibited the preovulatory surge of LH until after cessation of treatment. These hormonal changes suggest that BZA inhibited both the positive and negative feedback effects of estrogen on gonadotropins and the resulting increase in LH caused formation and persistence of ovarian cysts, which eventually transformed into benign ovarian granulosa cell tumors in the rat carcinogenicity study. These results also suggest that the reductions in pituitary and mammary gland tumors were attributed to BZA-related antagonism of endogenous estrogens at the estrogen receptors.

Cathepsin B mRNA and protein expression following contusion spinal cord injury in rats.

We provide the first data that cathepsin B (Cath B), a lysosomal cysteine protease, is up-regulated following contusion-spinal cord injury (SCI). Following T12 laminectomy and moderate contusion, Cath B mRNA and protein expression profiles were examined from 2 to 168 h post-injury in rats using real-time PCR and immunoblots, respectively. Contusion injury significantly increased [mRNA]Cath B in the injury site and adjacent segments over sham injury levels. While the largest [mRNA]Cath B induction (20-fold over naive) was seen in the injury site, the caudal segment routinely yielded [mRNA]Cath B levels greater than 10-fold over naive. Interestingly, sham injury animals also experienced mRNA induction at several time points at the injury site and in segments rostral and caudal to the injury site. Contusion injury also significantly elevated levels of Cath B proenzyme protein (37 kDa) over sham injury in the injury site (48, 72 and 168 h post-injury). Furthermore, significant protein increases of single and double chain Cath B (both active forms) occurred at the injury site at 72 and 168 h post-injury. Similar significant increases in Cath B protein levels were seen in areas adjacent to the injury site. The induction of Cath B mRNA and protein expression following contusion injury is previously undescribed and suggests that Cath B may potentially be involved in the secondary injury cascade, perhaps for as long as 1 week post-injury.