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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemopreventive activity of the aromatase inhibitors vorozole and 4-hydroxyandrostenedione were determined in the methylnitrosourea (MNU)-induced model of rat mammary tumorigenesis. Vorozole (5 and 2.5 mg/kg body wt) and 4-hydroxyandrostenedione (15 and 6 mg/rat) were administered daily (by gavage) to virgin female Sprague-Dawley rats starting at an age of 43 days. Seven days later animals were given a single dose of MNU. Following treatment with MNU, animals continued to be treated with vorozole and 4-hydroxyandrostenedione daily until the end of the experiment (100 days post MNU treatment). Vorozole at either dose proved to be a profound inhibitor of MNU-induced mammary tumors. Vorozole decreased tumor incidence from 100% to 10%, while simultaneously decreasing tumor multiplicity from 5 tumors per animal to 0.1 tumors per animal. This chemopreventive effect was accompanied by significant increases in body weight gain in the animals treated with vorozole when compared with control rats. In contrast, neither dose of 4-hydroxyandrostenedione had any effect on tumor incidence and only the higher dose slightly decreased tumor multiplicity.
Carcinogenesis 1994 Dec
PMID:Chemopreventive effects of the aromatase inhibitors vorozole (R-83842) and 4-hydroxyandrostenedione in the methylnitrosourea (MNU)-induced mammary tumor model in Sprague-Dawley rats. 800 Dec 34

The chemopreventive activity of the highly specific nonsteroidal aromatase inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced rat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.25 mg/kg body wt/day) were administered daily (by gavage) to female Sprague-Dawley rats starting at 43 days of age. Seven days later, the rats were given a single i.v. dose of MNU (50 mg/kg body wt). Rats were continually treated with vorozole until the end of the experiment (120 days post-MNU). Vorozole caused a dose dependent inhibition of mammary cancer multiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day) decreased cancer multiplicity by approximately 90%, and simultaneously decreased cancer incidence from 100 to 44%. The next two highest doses of vorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammary cancer multiplicity by 70-80%. Even the two lowest doses of vorozole (0.16 and 0.08 mg/kg body wt/ day) decreased cancer multiplicity -50%. Serum level determinations were performed on a variety of endpoints at either 4 or 24 h following the last dose of vorozole. Insulin-like growth factor (IGF)-1 levels were slightly, but significantly, increased by vorozole treatment. Vorozole induced striking increases in serum testosterone levels at 4 h at all the dose levels employed. Testosterone levels were significantly elevated over controls at 24 h in rats given the lower doses of vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lower than in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kg body wt/ day). This result presumably reflects the limited half-life of vorozole in rats. In a second series of experiments, the effects of limited duration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittent dosing with vorozole were determined. Treatment of rats with vorozole for limited time periods, from 3 days post-MNU administration until 30 or 60 days post-MNU treatment, resulted in significant delays in the time to appearance of palpable cancers. However, these limited treatments did not greatly affect the overall incidence or multiplicity of mammary cancers when compared with the MNU controls at the end of the study (150 days post-MNU). Finally, the effects of intermittent dosing with vorozole (2.5 mg/kg body wt/day) were examined. Rats were administered cycles of vorozole daily for a period of 3 weeks followed by treatment with the vorozole vehicle for the next 3 weeks (total of four cycles). Although this intermittent treatment did inhibit the appearance of new tumors during each of the periods that vorozole was administered, it did not cause regression of palpable cancers.
Carcinogenesis 1998 Aug
PMID:Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model. 974 27

Vorozole (Vz) is a competitive non-steroidal inhibitor of aromatase, which has been used to treat breast cancer in postmenopausal women and in various chemoprevention pre-clinical studies. Recently, we assessed the inhibitory effect of Vz on MNU-induced mammary carcinogenesis (Lubet et al., 1994), as well as on the progression of mammary tumors (Lubet et al., 1998). In this study we evaluated the effects of Vz on tumor growth, serum estradiol, cell proliferation, apoptotic and non-apoptotic cell death to determine whether any of these 'surrogate' markers might reflect the efficacy of various doses of Vz. Vz at doses of 2.5 (Hi), 0.32 (Md), and 0.08 (Lo) mg/kg body weight induced complete (100%), 60%, and 20% regression of mammary tumors, respectively. Vz at Hi and Md doses caused a decrease in serum estradiol within the first two days of treatment, and the estradiol values remained low with additional treatment for 4 and 10 days. When Vz was administered to animals bearing palpable tumors a time and dose-dependent decrease in the proliferating cells (BrdU-L1) was observed. The percentage of apoptotic cells (A1) sharply increased 2 days after initiation of Vz treatment and then decreased followed by an increase in non-apoptotic dead cells. Interestingly even the Lo dose of Vz, which was only moderately effective in suppressing tumor growth, decreased cell proliferation and increased cell death in the peripheral tumor areas at 4 and 10 days after initiation of treatment. The time- and dose-dependent alterations in various cell parameters suggest two different phases of Vz-induced cellular responses: (1) an early phase (2-4 days of treatment) with a sharp increase in apoptotic cells and decrease in proliferating cells, and (2) a later phase (10 days) with disintegration of tumor parenchyma, increase in non-apoptotic dead cells, and decrease in apoptotic cells. The dose-dependent decrease in proliferating cells and increase in apoptotic and non-apoptotic cell death in Vz-treated animals suggest that these biomarkers might be used as potential surrogate endpoints for efficacy in breast cancer chemoprevention and therapy studies with aromatase inhibitors.
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PMID:Cellular responses of mammary carcinomas to aromatase inhibitors: effects of vorozole. 1084 74

Vorozole, a nonsteroidal aromatase inhibitor, impedes the post-initiation stage of chemically induced mammary carcinogenesis. While various aspects of vorozole's effects on mammary carcinoma development have been investigated, little attention has been directed to determining the estrogen receptor (ER) and progesterone receptor (PR) content of mammary carcinomas that arise despite vorozole treatment. Female Sprague-Dawley rats were given an i.p. injection of 50mg MNU/kg body weight at 21 days of age and placed on diet supplemented with 0 or 3 mg vorozole/kg, which had no effect on mammary tumor development. Histologically confirmed carcinomas were evaluated for ER and PR by immunohistochemistry. In the control group, 78.8% of carcinomas were ER positive with an ER content ranging from 13.8 to 40.0%, similar to ER content of mammary ductal epithelial cells from non-carcinogen treated animals. PR content ranged from 4.4 to 45.2% and also was similar to levels of PR observed in ductal epithelial cells. ER was not correlated with PR in mammary carcinomas (r = 0.05, p > 0.80), whereas there was a significant correlation in ductal epithelium (r = 0.86, p = 0.006). In vorozole-treated rats, no ER negative carcinomas were observed and overall ER expression by vorozole was elevated (p < 0.03). All carcinomas from vorozole-treated rats expressed PR (2.5-60.2%) and correlation between ER and PR content was numerically greater in carcinomas from vorozole-treated animals (r = 0.42, p = 0.09). These data, which are considered hypothesis generating, provide evidence that low doses of vorozole in the diet select for mammary carcinomas with an increased ER positive phenotype.
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PMID:Effect of the aromatase inhibitor vorozole on estrogen and progesterone receptor content of rat mammary carcinomas induced by 1-methyl-1-nitrosourea. 1180 81