Induced Rat Mammary Carcinoma Research Articles

141 Therapy of 7, 12-DMBA induced rat mammary carcinomas with combinations of diazoxide and tamoxifen or medroxyprogesterone acetate

141 Therapy of 7, 12-DMBA induced rat mammary carcinomas with combinations of diazoxide and tamoxifen or medroxyprogesterone acetate

High-affinity anti-oestrogen binding site distinct from the oestrogen receptor.

Non-steroidal anti-oestrogens such as tamoxifen, CI 628, nafoxidine and clomiphene, are structurally related synthetic compounds that antagonize the effects of oestrogen on its target tissues, and this activity has led to the use of tamoxifen to treat advanced breast cancer. All these compounds inhibit the binding of tritiated oestradiol to cytosol from oestrogen target tissues, suggesting that anti-oestrogens bind to the oestrogen receptor. This is supported by reports that in the rat uterus and dimethyl-benz (alpha)-anthracene (DMBA)-induced rat mammary carcinoma, oestradiol and anti-oestrogens bind directly to the same number of saturable binding sites. Furthermore, oestrogens and anti-oestrogens are mutually competitive for binding to these sites. It has thus been generally accepted that the anti-oestrogens exert most of their effects through the specific oestrogen receptor. We now report a further high-affinity, anti-oestrogen binding site which may have a role in regulating the effects of non-steroidal anti-oestrogens.

Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA -induced rat mammary carcinoma model

The antitumour activity of monohydroxytamoxifen has been compared with tamoxifen in the DMBA-induced rat mammary carcinoma model. In general antioestrogen therapy between 30 and 60 days after DMBA administration was more successful than therapy between 60 and 90 days after DMBA. Although monohydroxy-tamoxifen was a more potent antioestrogen than tamoxifen and equivalent dosage regimens were more effective at reducing cytoplasmic oestrogen receptor concentrations in the ovariectomized rat uterus, tamoxifen appeared to be a more potent antitumour agent. The administration of 4 weekly courses of tamoxifen ( 0.2, 3, 50 or 800 μg daily, 5 times a week) starting 30 days after DMBA produced a dose-related delay in tumour appearance and a decrease in tumour numbers. By contrast, monohydroxytamoxifen ( 0.012, 0.2, 3 or 50 μg daily, 5 times a week) was only weakly active at delaying tumour appearance although tumour numbers were reduced. Most of the tumours that developed in groups previously treated with antioestrogens regressed upon ovariectomy of the host. From studies in ovariectomized rats, tamoxifen was found to have long term effects upon the uterus whereas equivalent doses of monohydroxytamoxifen were only effective for a short period after the cessation of therapy. These data suggest that mammary tumour development is best inhibited in the constant presence of an antioestrogen i.e., biological half-life, as well as potency, is important for antitumour activity. The principle was exemplified by a reduction in the number and sizes of mammary tumours developing during continuous therapy with monohydroxytamoxifen ( 3 or 50 μg daily, 5 times a week) starting 30 days after DMBA. Overall it was clear that antioestrogens do not destroy all the foci of hormone dependent tumour cells and long courses of therapy or the use of other antihormonal methods e.g., ovariectomy, are essential to control tumour growth.

DNA Labeling Index and Structure of the Rat Mammary Gland as Determinants of Its Susceptibility to Carcinogenesis<xref ref-type="fn" rid="FN2">2</xref>

In a study of 7,12-dimethylbenz[a]anthracene (OMBA)-induced rat mammary carcinomas, which arise from the terminal end-buds (TEB) and terminal ducts (TD) of the mammary gland, and benign lesions such as hyperplastic alveolar nodules and adenomas, which arise from the alveolar buds (AB) of the gland, we correlated the number of TEB, TD, and AB and their DNA labeling indexes at the time of DMBA administration with the number and type of mammary gland tumors induced by the carcinogen. Young virgin (55-day-old), old virgin (180-day-old), and multiparous (180-day-old) noninbred Sprague-Dawley rats were inoculated iv with [3H]thymidine. Simultaneously, a similar group received one intragastric dose of DMBA. The group given [3H]thymidine was killed 1 hour after injection. All mammary glands were processed for either wholemount or autoradiography. The number of TEB, TD, AB, and lobules per square millimeter were counted in wholemount preparations, and the DNA labeling index in the epithelial cells of these structures was determined. These results were compared with the number and type of tumors developed by the animals of the second group. The mammary glands of young virgin rats that contained the highest number of TEB, TD, and labeled cells had 100% incidence of carcinomas. The glands of old virgin rats had fewer TEB and TD and fewer labeled cells, and these rats developed fewer carcinomas (63%). Glands of multiparous rats contained no TEB, a small number of TD, and few labeled cells; these rats had the lowest Incidence of carcinomas (21%). The results demonstrated that the susceptibility to carcinogens is correlated to the density of TEB and TD and their DNA labeling indexes.

乳腺腫瘍におけるEstrogen binding proteinに関する研究

Estrogen binding protein (EBP) in mammary tumor was studied in DMBA induced rat mammary carcinoma, Shionogi carcinoma 115, Shionogi carcinoma 42 and human mammary tumor by use of 3H-estradiol.Free and bound estradiol was separated by Sephadex G-25.Specific EBP was calculated 4.5S by sucrose gradient centrifugation. Non-specific EBP was observed in the 3.2S-3.6S region of the ultracentrifugal analysis.Specific EBP was migrated to anodic region of α- or β-position in disc electrophoresis.

TAMOXIFEN AS AN ANTI-TUMOUR AGENT: EFFECT ON OESTROGEN BINDING

Tamoxifen (ICI 46,474) has been shown to possess anti-tumour properties in the dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinoma model. During tamoxifen therapy the binding of [3H]oestradiol in vivo to uterine (P less than 0-001), vaginal (P less than 0 X 01) and tumour (P less than 0-001) tissues was significantly reduced. Tamoxifen therapy was without effect on the binding of [3H]oestradiol in heart tissue. The determination of specific oestrogen-binding components in vitro was significantly reduced (P less than 0-01) in tumours from tamoxifen-treated rats and tamoxifen inhibited the binding of [3H]oestradiol to 8S oestrogen-binding components, derived from rat uteri and DMBA-induced tumours, in vitro.

243. Antitumour activity of the antiestrogen ICI 46,474 (Tamoxifen) in the dimethylbenzanthracene (DMBA)—induced rat mammary carcinoma model

243. Antitumour activity of the antiestrogen ICI 46,474 (Tamoxifen) in the dimethylbenzanthracene (DMBA)—induced rat mammary carcinoma model