Dual action of high estradiol doses on MNU-induced prostate neoplasms in a rodent model with high serum testosterone: Protective effect and emergence of unstable epithelial microenvironment.

BACKGROUND: Estrogens are critical players in prostate growth and disease. Estrogen therapy has been the standard treatment for advanced prostate cancer for several decades; however, it has currently been replaced by alternative anti-androgenic therapies. Additionally, studies of its action on prostate biology, resulting from an association between carcinogens and estrogen, at different stages of life are scarce or inconclusive about its protective and beneficial role on induced-carcinogenesis. Thus, the aim of this study was to determine whether estradiol exerts a protective and/or stimulatory role on N-methyl-N-nitrosurea-induced prostate neoplasms. METHODS: We adopted a rodent model that has been used to study induced-prostate carcinogenesis: the Mongolian gerbil. We investigated the occurrence of neoplasms, karyometric patterns, androgen and estrogen receptors, basal cells, and global methylation status in ventral and dorsolateral prostate tissues. RESULTS: Histopathological analysis showed that estrogen was able to slow tumor growth in both lobes after prolonged treatment. However, a true neoplastic regression was observed only in the dorsolateral prostate. In addition to the protective effects against neoplastic progression, estrogen treatment resulted in an epithelium that exhibited features distinctive from a normal prostate, including increased androgen-insensitive basal cells, high androgens and estrogen receptor positivity, and changes in DNA methylation patterns. CONCLUSIONS: Estrogen was able to slow tumor growth, but the epithelium exhibited features distinct from a normal prostatic epithelium, and this unstable microenvironment could trigger lesion recurrence over time.

Histamine receptors in an experimental mammary carcinoma.

An experimental mammary carcinoma was induced in Sprague-Dawley rats by the ip administration of N-nitroso-N-methylurea (NMU) in three doses of 50 mg/kg. In order to study the expression of histamine receptors in these experimental tumors, the presence of specific binding sites for histamine was studied. Using [3H]-histamine as a radioligand, two specific binding sites were characterized on the cell membrane. The first site, of high affinity, Kd = 4 +/- 2 nM, was further characterized as an H2 type using [3H]-cimetidine and [3H]-tiotidine as radioligands and by displacement experiments with different histamine agonists and antagonists. The second one of low affinity, Kd = 35 +/- 14 nM, needs further characterization. The determination of cAMP levels showed that histamine and the H2 agonist dimaprit, produced a significant decrease in the nucleotide concentration 6 minutes after stimulation, in a response that was specifically abolished by H2 antagonists. Based on these results, we conclude that neoplastic cells from NMU induced tumors express H2 histamine membrane receptors which are coupled to a transductional pathway different from cAMP production, which may be involved in the regulation of tumor growth.

Postnatal ontogeny of gamma glutamyltranspeptidase activity of pancreas in essential fatty acid deficient rats treated with nitrosomethylurea.

The effect of essential fatty acid deficiency and nitrosomethylurea treatment on postnatal levels of pancreatic gamma-glutamyltranspeptidase was studied. A significant increase of gamma-glutamyltranspeptidase activity and changes in fatty acid composition were observed in essential fatty acid deficient rats, from the 14th day of life on. Pancreatic gamma-glutamyltranspeptidase of nitrosomethylurea injected rats in essential fatty acid deficiency and controls was significantly diminished at the 30th day, with no significant differences in both nutritional conditions. The results indicated: 1. Concomitant changes in gamma-glutamyltranspeptidase activity and fatty acid composition of rat pancreas in essential fatty acid deficiency, 2. A significant reduction of pancreatic gamma-glutamyltranspeptidase activity following a single intraperitoneal injection of nitrosomethylurea at day one of life and 3. No interacting effects of essential fatty acid deficiency and nitrosomethylurea on gamma-glutamyltranspeptidase activity of rat pancreas.

A Feulgen microspectrophotometric study of the DNA content of essential fatty acid-deficient rat pancreas treated with nitrosomethylurea.

Microspectrophotometric DNA measurements in exocrine pancreas of essential fatty acid-deficient (EFAD) and EFA-sufficient (EFAS) rats which received a single intraperitoneal injection of the carcinogen nitrosomethylurea (NMU) or saline (SAL) was the subject of the present report. The DNA content of acinar pancreatic cells of SAL-injected EFAD and EFAS rats was diploid. NMU-induced pancreatic focal acinar cell hyperplasia (FACH) had one main cell population with a diploid content, whereas in the intervening parenchyma there were diploid and tetraploid cells. The number of tetraploid cells was smaller in EFAD rat pancreas than in EFAS indicating a diet dependent effect. NMU-induced FACH had a diploid distribution pattern indicating that cells are in a G1, quiescent phase, contrasting with AZA-induced similar lesions which showed an abnormal ploidy. It remains to be established whether DNA phenotypic traits of NMU and AZA induced FACH reflect the neoplastic potentials of both types of lesions. The decreased number of tetraploid cells in EFAD rat pancreas is in keeping with data indicating a promoting effect of the EFA linoleic and arachidonic acids on growth rate of certain cell populations in vitro.