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Biomedical subjects

R G Mehta

Publications and source records attributed to R G Mehta.

At least 73 records · Page 4Linked to original sources
PubMed1982

Retinoic acid binding proteins and steroid receptor levels in human breast cancer.

Samples of 31 human breast cancer tissues were examined for the presence or absence of cytosolic retinoic acid binding proteins (cRABP), estrogen receptors (ER) and progesterone receptors (PR). cRABP were detected as specifically sedimenting 2S components on sucrose density gradient. Specific binding under the 2S region for cRABP and under the 8S region for ERR and PR were determined. The levels of cRABP ranged from less than 1 pmol to 14 pmol per mg of cytosol protein. Tumors containing less than 3 pmol cRABP were designed as low cRABP; tissues were considered ER- and PR- when the receptor levels were less than 10 fmol/mg protein. Approximately 60% of primary and metastatic tumors examined contained high cRABP. Tumors with well differentiated histopathology exhibited increased levels of cRABP. There was no significant correlation between the presence or absence of steroid receptors and cRABP in human mammary tumors.

Breast Neoplasms↗
PubMed1982

Correlation between retinoid inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis and levels of retinoic acid binding proteins.

A correlation was made between the ability of retinoids to suppress N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis and the levels of cytosolic retinoic acid binding proteins (cRABP) in the cytosol of MNU-induced mammary tumors. Although retinyl acetate and N-(4-hydroxyphenyl)-retinamide were found to be effective inhibitors of mammary carcinogenesis in intact hosts, both retinoids were significantly more active in ovariectomized rats than in intact animals. Quantitative analysis of cRABP in the tumors indicated that mammary cancers arising in animals which were ovariectomized one week after MNU administration contained significantly increased concentrations of cRABP compared to cancers appearing in intact rats. In addition, when animals bearing palpable mammary tumors were ovariectomized, the tumors which continued to grow contained significantly higher levels of cRABP than did tumors which stopped growing or regressed. These data suggest that the selective inhibition of ovarian hormone-independent mammary cancer by retinyl acetate and N-(4-hydroxyphenyl)retinamide may be mediated through an increased level of cRABP in tumor cells of ovariectomized hosts.

Animals↗
PubMed1982

Enhanced inhibition of mammary carcinogenesis by combined treatment with N-(4-hydroxyphenyl)retinamide and ovariectomy.

Bilateral ovariectomy and dietary administration of the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) are both effective inhibitors of chemical carcinogenesis in the rat mammary gland. The present study was designed to determine whether an enhanced inhibitory effect is obtained with combined ovariectomy and 4-HPR administration, compared to either treatment alone. In separate experiments, 50-day-old virgin female Sprague-Dawley rats received either a single i.v. injection of 50 mg N-methyl-N-nitrosourea per kg body weight or a single intragastric dose of 20 mg 7,12-dimethylbenz(a)anthracene. The experimental design was the same in both the N-methyl-N-nitrosourea and 7,12-dimethylbenz(a)anthracene experiments: Group 1, 25 intact rats, placebo diet; Group 2, 25 intact rats, supplement of 782 mg 4-HPR per kg diet; Group 3, 50 ovariectomized rats, placebo diet; Group 4, 50 ovariectomized rats, supplement of 782 mg 4-HPR per kg diet. Feeding of the 4-HPR supplement was begun 7 days after carcinogen administration; ovariectomy was performed 7 days post-7,12-dimethylbenz(a)anthracene or 14 days post-N-methyl-N-nitrosourea. In both experiments, combined ovariectomy plus 4-HPR was significantly more active in suppressing mammary cancer induction than was either manipulation alone. 4-HPR was a more effective inhibitor of carcinogenesis in ovariectomized rats than in intact animals. These data indicate that 4-HPR is highly effective in inhibiting ovarian hormone-independent cancers and suggest that retinoid inhibition of mammary carcinogenesis does not involve an influence on ovarian hormone action.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Hormonal regulation of retinoic acid-binding proteins in the mammary gland.

A cytosolic retinoic acid-binding (RAB) protein that sediments specifically as a 2S component on sucrose density gradients was detected in the mammary glands of virgin, pregnant and lactating rats. Mammary cytosol from pregnant rats contained significantly higher concentrations of cytosolic RAB protein than did cytosol from either virgin or lactating rats. The glands of pregnant animals exhibited increased concentration of cytosolic RAB protein during the first 5 days of pregnancy, and a steady decline was observed thereafter. The concentration of cytosolic RAB protein dropped to the value observed during lactation on the day 20 of pregnancy. Moreover, throughout lactation, low concentrations of cytosolic RAB protein were maintained. Daily treatment of virgin and lactating animals with 5 micrograms of oestradiol-17 beta for 1 week increased cytosolic RAB protein to concentrations comparable with those seen in pregnant rats. Progesterone, however, did not affect the mammary cytosolic RAB protein content of virgin rats. These results suggest hormonal involvement in the regulation of cytosolic RAB protein concentration of mammary gland during differentiation.

Animals↗
PubMed1981

Retinoid binding in normal and neoplastic mammary tissue.

The inhibitory effect of dietary supplementation of certain retinoids on mammary carcinogenesis in the rat has been reported from our laboratory. Specific cytosolic retinoic acid binding proteins (cRABP) as well as retinol binding proteins sedimenting as 2S components have been detected in the mammary tissue during normal and neoplastic differentiation. Relatively higher levels of cRABP were observed in the mammary glands from pregnant animals as well as in ovarian hormone independent tumors; whereas in glands obtained from lactating rats and in hormone dependent tumors, lower levels of cRABP were evident. Exogenous treatment of such animals with estradiol-17 beta enhanced the levels of cRABP. The results indicate a possible correlation between endocrine and retinoid function in both normal and neoplastic differentiation of mammary tissue. [3H]retinoic acid-RABP complex, under appropriate conditions, translocates into th nucleus. Unbound [3H]retinoic acid, however, failed to associate with the nuclear sites. Additional studies indicate a possible selective inhibition of ovarian hormones independent tumors by the retinoids.

Animals↗
PubMed1980

Androgen receptors in chemically-induced colon carcinogenesis.

Cytoplasmic extracts (105,000 x g supernatants) prepared from the colon of 1,2-dimethylhydrazine hydrochloride (DMH) treated male BD-IX rats bound 3H-5 alpha-dihydrotestosterone (DHT) with high affinity (Kd = 3 x 10(-9) M) and low capacity (n = 20 fmoles/mg protein). Unoccupied saturable binding sites were not detected in normal intact colon but were observed in colons from gonadectomized rats. DHT receptors were present in both the ascending and descending segments of the colon. The DHT binding components sedimented as 7--8S species on linear sucrose density gradients and were effectively displaced by cyproterone acetate, but not by progesterone. Forty percent of the DMH-induced colon tumors also bound DHT with high affinity and limited capacity. These results suggest that the sex steroids are involved in carcinogen-induced colon tumorigenesis, and the action is mediated by their association with sex steroid specific receptors.

Animals↗
PubMed1980

Distribution of retinoic acid-binding proteins in normal and neoplastic mammary tissues.

Cellular retinoic acid-binding proteins were detected in chemically induced mammary tumors using sucrose density gradient analysis. Unlabeled retinoic acid did not displace nonspecific binding in the 5S region but was, however, a competitive inhibitor for the specifically binding 2S component. Mammary gland cytosol fractions from both 1-methyl-1-nitrosourea-treated and untreated as well as from lactating rats contained low levels of retinoic acid-binding proteins. 1-Methyl-1-nitrosourea treatment did not result in the increased number of binding sites. Thus, the increase in the levels of binding proteins in tumors most probably occurred during tumor development and probably was not a result of the carcinogen per se. Retinoids which have been shown to be effective in the chemoprevention of mammary carcinogenesis only partially competed for the binding sites, indicating that they may be metabolized prior to their action as an active chemopreventive agent.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Inhibition of DNA synthesis by retinyl acetate during chemically induced mammary carcinogenesis.

The effect of retinoids on DNA synthesis was studied in the female Sprague-Dawley rat. Animals were treated with either solvent, 7,12-dimethylbenz(a)anthracene, or 1-methyl-1-nitro-sourea at 50 days of age and were placed on either placebo or retinyl acetate diet at 57 days of age. [3H]Thymidine incorporation into purified DNA isolated from mammary parenchymal cells was determined. Retinyl acetate effectively inhibited mammary cell DNA synthesis in both 1-methyl-1-nitrosourea- and 7,12-dimethylbenz(a)anthracene-treated animals; however, DNA synthesis in solvent-treated animals was unaffected.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Nuclear interaction of Fusarium mycotoxins with estradiol binding sites in the mouse uterus.

By using cell-free preparations of uteri obtained from immature BALB/c mice, it was demonstrated that zearalenone and zearalanol, Fusarium mycotoxins, inhibited [3H]estradiol-17 beta binding to specific sites in cytosol. Significant inhibition was noted from zearalenone at 4 x 10(-6) M and from zearalanol at 4 x 10(-7) M. Unlabeled mycotoxins (5 x 10(-6) M) incubated with intact uteri caused translocation of specific estrogen binding sites into nuclei that were exchangeable with [3H]estradiol-17 beta. Zearalanol was more effective in this regard than zearalenone. Ability of the mycotoxins to compete with estradiol-17 beta for the cytosol receptor and to cause translocation of the receptor to the nucleus in general is correlated with their biological activity. These data suggest that the uterotrophic effects of Fusarium mycotoxins are mediated through their association with estrogen receptors in the uterus.

Animals↗
PubMed1976

Steroid-binding proteins of the mammary gland and their clinical significance in breast cancer.

Differentiation and development of the mammary gland are influenced by estrogens, glucocorticoids, and progesterone. Specific binding sites for each of these classes of steroid hormones have been characterized in vivo and in cell-free preparations of lactating mammary gland of the rat. These properties were compared with those of steroid-binding proteins in the R3230AC and dimethylbenz[a]anthracene-induced mammary tumors of the rat and of human breast carcinomas. The binding components that were protein in nature were more concentrated in tissue from lactating than from virgin or pregnant rats. The steroid-binding capacities of mammary tumors were highly variable. Using a dextran-coated charcoal procedure, the rate constants of 3H-ligand association with specific binding sites were temperature dependent. Ligand specificity indicated that [3H]estradoil-17beta(3H-E) binding was inhibited only by estrogens, whereas [3H]triamcinolone acetonide (3 H-TA) was blocked by glucocorticoid/s and progesterone. Likewise, [3H]progesterone (3H-P) binding was inhibited by progestins and certain glucocorticoids. Incubation of minced mammary gland with 3H-steroid in the presence and absence of unlabeled competitor demonstrated specific binding sites in cytoplasm that were translocated to nuclei in a tempreature-dependent fashion. Using a steroid-exchange procedure both DEX and TA inhibited 3H-P binding to exchangeable sites that were loaded previously with unlabeled progesterone. These data suggest that certain glucocorticoid and progesterone binding sites were translocated simultaneously to nuclei. Administration in vivo of either 3H-E or 3H-TA indicated binding in cytoplasm and subsequent translocation to nuclei.

Animals↗
PubMed1975

Action of growth-promoting hormones on macromolecular biosynthesis during lobulo-alveolar development of the entire mammary gland in organ culture.

The entire 2nd thoracic mammary gland of the immature virgin BALB/c mouse was stimulated to full lobulo-alveolar (LA) growth after 120 h organ culture in hormone supplemented medium. The minimal hormonal combination required was insulin (I) + prolactin (Prl) + aldosterone (A). The corticosteroid was replaceable by oestradiol-17beta (E) + progesterone (P). The combination I alone or I + the steroid hormone(s) failed to induce the LA development and similar results were also evident in presence of Prl + the steroids. Incubation of the glands in medium with I + Prl + A activated a sequential rise of RNA, protein and DNA synthesis. A near maximal increase of RNA synthesis was present at 48 h in the medium with I + Prl, addition of the steroid hormones did not show further stimulatory effect. Supplementation of the medium with I + Prl and the adrenal or the ovarian steroids was needed for maximal activation of protein synthesis at 72 h and DNA replication at 96 h. The medium with I alone did not show a substantial rise of macromolecular biosynthesis in the mammary gland in organ culture. The highest level of DNA polymerase activity was observed at 72 h in glands cultivated in medium with I + Prl and A or E + P. Only a modest increase of DNA polymerase activity was present in glands cultivated with I alone or I + Prl. Prior treatment of the glands (cultivated with I + Prl + A) with actinomycin D or puromycin resulted into 44 and 40% reduction of DNA polymerase activity suggesting hormone-induced synthesis of the enzyme before the rise of DNA synthesis in the mammary cells at 96 h in organ culture. Significance of these results with respect to the action of the "growth-promoting" hormones in the mammary gland in organ culture and in the animal has been discussed.

Aldosterone↗
PubMedDate not supplied

Effect of all-trans-retinoic acid on nuclear RNA polymerase activity in chemically-induced rat mammary tumors.

In the present study the effect of all-trans-retinoic acid (RA) on nuclear RNA polymerase activity in N-methyl-N-nitrosourea (MNU)-induced mammary tumors was investigated. Three experimental protocols were used. (1) The tumor mince was incubated with 1 microM RA for 30 min at 30 degrees C; the RNA polymerase activity was measured in the purified nuclei and compared with control nuclei. (2) In order to evaluate the influence of retinoic binding protein on enzyme activity, mammary tumor nuclei were incubated with RA bound cytosolic retinoic acid binding protein complex (RA-CRABP) at 25 degrees C for 30 min. This step allows the complex to translocate into the nuclei. The enzyme activity in these nuclei was compared with the nuclei pre-incubated with buffer or cytosol. (3) Finally, the influence of the addition of RA-CRABP complex directly into the RNA polymerase reaction mixture was determined and compared with appropriate controls. Results indicated that the RNA polymerase activity in the nuclei of RA treated tissue as well as in the nuclei subsequent to the translocation step was significantly reduced. However, the addition of RA-CRABP into the reaction mixture did not alter the enzyme activity. These results suggest that alteration of RNA polymerase activity may be an essential step in the retinoid action in mammary tissues.

Animals↗
PubMedDate not supplied

Discovery of novel inducers of cellular differentiation using HL-60 promyelocytic cells.

Non-physiological inducers of terminal differentiation have been used as novel therapies for the prevention and therapy of cancer. We have used cultured HL-60 promyelocytic cells to monitor differentiation, proliferation and cell death events as induced by a large set of extracts derived from plants. Screening of more than 1400 extracts led to the discovery of 34 with potent activity (ED50 <8 mg/ml). Bioassay-guided fractionation led to the isolation of zapotin and 2',5,6-trimethoxyflavone as active principles from Casimiroa edulis, dibenzyltrisulfide and 2-[(phenylmethyl)dithio]ethanol as active principles from Petiveria alliacea, and desmethylrocaglamide from Aglaia ponapensis. Zapotin demonstrated the most favorable biological profile in that induction of differentiation correlated with proliferation arrest, and a lack of cytotoxicity. We conclude that the HL-60 cell model is a useful system for the discovery of novel pharmacophores with potential to suppress the process of carcinogenesis, and that flavonoids may be especially useful in this capacity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Influence of thiols and inhibitors of prostaglandin biosynthesis on the carcinogen-induced development of mammary lesions in vitro.

Mouse mammary gland undergoes physiological changes, comparable to that in the animal, under appropriate hormonal conditions in organ culture. Moreover, they form mammary lesions when exposed to the carcinogen, dimethylbenz(a)anthracene (DMBA) for a short duration. This organ culture system was utilized in the present of study to evaluate activity of two groups of potential chemopreventive agents. Activity of inhibitors of prostaglandin synthesis and thiols was determined at five concentrations. The average incidence of mammary lesions induced by DMBA was 60%, oltipraz oxithiazolidine, thioctic acid and N-acetylcysteine were effective at different concentrations, whereas diallyldisulfide, sulfasalazine and ajoene were marginally effective. Within the inhibitors of prostaglandin synthesis category, aspirin, ibuprofen and indomethacin were effective, whereas dipyridamol, piroxicam and pentoxyphyllin were ineffective. The results correlated well with the known in vivo effects of these agents on chemically induced carcinogenesis of mammary gland. The study provides evidence for the use of mammary gland organ culture as a screening total system for prediction of effective chemopreventive agents against mammary carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Characterization of effective chemopreventive agents in mammary gland in vitro using an initiation-promotion protocol.

Mouse mammary glands respond to carcinogen stimulus to form mammary lesions in organ culture. Prevention of the formation of mammary lesion has been utilized as a test to evaluate the effectiveness of a variety of classes of agents. In the present study we determined whether the effective chemopreventive agents are active against initiation or the promotion phase of lesion development. Mammary glands were subjected to 24 hours exposure to 2 mg/ml dimethylbenz (a) anthracene (DMBA) followed by a 5 day exposure to 7,12-tetradecanoyl phorbol - 13 - acetate (TPA). This treatment protocol allows one to study initiation and promotion aspects of lesion development. Chemopreventive agents effective when present prior to the carcinogen were considered as anti-initiators, whereas agents effective when present after the DMBA treatment along with TPA were considered as anti-promoters. Within the chemopreventive agents evaluated, limonene, oltipraz, aspirin, curcumin and b-sitosterol were anti-initiators. Esculatin, thiolutin, silymarin, DHEA and a few others were found to be anti-promoters. Results presented in this report can be utilized to study the efficacy of these agents in vivo.

9,10-Dimethyl-1,2-benzanthracene↗