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Biomedical subjects

M Lippman

Publications and source records attributed to M Lippman.

At least 73 records · Page 4Linked to original sources
PubMed1977

Glucocorticoid receptors in purified subpopulations of human peripheral blood lymphocytes.

On the premise that the differential effects of glucocorticoids on various aspects of the immune response may be mediated by differences in the glucocorticoid receptors in the effector cells, subpopulations of human peripheral blood lymphocytes were examined for these receptors as well as for glucocorticoid responsiveness. Purified T and non-T lymphocytes, when studied by a sensitive whole cell assay technique, contained equivalent amounts of specific glucocorticoid receptor, which, by binding affinity and specificity measurements, were indistinguishable from each other. Furthermore, under in vitro incubation conditions, macromolecular synthesis in both of these cell populations was inhibited by glucocorticoid at concentrations which saturated the receptor sites. It is concluded that the putative differential effects of glucocorticoids on T and non-T lymphocyte-associated functions are probably not mediated by differences in the glucocorticoid receptors in these cell populations.

Cell Separation↗
PubMed1977

Effects of estrone, estradiol, and estriol on hormone-responsive human breast cancer in long-term tissue culture.

The effects of estrone, estradiol, and estriol on MCF-7 human breast cancer are compared. In this estrogen-responsive cell line, all three estrogens are capable of inducing equivalent stimulation of amino acid and nucleoside incorporation. Estriol is capable of partially overcoming antiestrogen inhibition with Tamoxifen (lCl 46474), even when antiestrogen is present in 1000-fold excess. Antiestrogen effects are completely overcome by 100-fold less estriol. Studies of metabolism of estrogens by MCF-7 cells revealed no conversion of estriol to either estrone or estradiol. All three steroids bind to a high-affinity estrogen receptor found in these cells. The apparent dissociation constant is lower for estradiol than for estrone and estriol, but all three bind to an equal number of sites when saturating concentrations are used. Tritiated estrogens used in binding studies were shown to be radiochemically pure. We conclude that estriol can bind to estrogen receptor and stimulate human breast cancer in tissue culture. Our data do not support an antiestrogenic role for estriol in human breast cancer.

Binding, Competitive↗
PubMed1976

A demonstration of androgen and estrogen receptors in a human breast cancer using a new protamine sulfate assay.

Separate receptors for estrogen and androgen are demonstrated in cells from metastic human breast cancer. By criteria of binding affinity, number of binding sites, and specificity of the receptor for different steroids, the receptors are shown to be distinguishable. The protamine sulfate receptor assay technique employed allows both kinds of receptor to be quantified conveniently and reproducibly without interference by plasma steroid-binding components.

Binding Sites↗
PubMed1976

The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture.

We have established or characterized six lines of human breast cancer maintained in long-term tissue culture for at least 1 year and have examined these lines for estrogen responsiveness. One of these cell lines, MCF-7, shows marked stimulation of macromolecular synthesis and cell division with physiological concentrations of estradiol. Antiestrogens are strongly inhibitory, and at concentrations greater than 3 X 10(-7) M they kill cells. Antiestrogen effects are prevented by simultaneous treatment with estradiol or reversed by addition of estradiol to cells incubated in antiestrogen. Responsive cell lines contain high-affinity specific estradiol receptors. Antiestrogens compete with estradiol for these receptors but have a lower apparent affinity for the receptor than estrogens. Stimulation of cells by estrogens is biphasic, with inhibition and cell death at concentrations of 17beta-estradiol or diethylstilbestrol exceeding 10(-7) M. Killing by high concentrations of estrogen is probably a nonspecific effect in that we observe this response with 17alpha-estradiol at equivalent concentrations and in the otherwise unresponsive cells that contain no estrogen receptor sites.

Binding Sites↗
PubMed1976

The effects of glucocorticoids and progesterone on hormone-responsive human breast cancer in long-term tissue culture.

Glucocorticoids, at physiological concentration, inhibit cell division and thymidine incorporation in three lines of human breast cancer maintained in long-term tissue culture. At steroid concentrations sufficient to inhibit thymidine incorporation 50%, little or no effect is seen on protein synthesis 48 hr after hormone addition. All three of these lines are shown to have glucocorticoid receptors demonstrable by competitive protein binding assays. Receptors are extensively characterized in one line by sucrose density gradient analysis and binding specificity studies. Good correlation between receptor-binding specificity and biological activity is found except for progesterone, which binds to glucocorticoid receptor but is noninhibitory. Cross-competition and quantification studies demonstrate a separate receptor for progesterone. This receptor has limited binding specificities restricted largely to progestational agents, whereas the glucocorticoid receptor bound both glucocorticoids and progesterone. Two other human breast cancer lines neither contain glucocorticoid receptor nor are inhibited by glucocorticoids. It is concluded that in some cases glucocorticoids can directly limit growth in human breast cancer in vitro without requiring alterations in other trophic hormones.

Binding Sites↗
PubMed1976

The effects of androgens and antiandrogens on hormone-responsive human breast cancer in long-term tissue culture.

We have examined five human breast cancer cell lines in continuous tissue culture for androgen responsiveness. One of these cell lines shows a 2- to 4-fold stimulation of thymidine incorporation into DNA, apparent as early as 10 hr following androgen addition to cells incubated in serum-free medium. This stimulation is accompanied by an acceleration in cell replication. Antiandrogens [cyproterone acetate (6-chloro-17alpha-acetate-1,2alpha-methylene-4,6-pregnadiene-3,20-dione) and R2956 (17beta-hydroxy-2,2,17alpha-trimethoxyestra-4,9,11-triene-1-one)] inhibit both protein and DNA synthesis below control levels and block androgen-mediated stimulation. Prolonged incubation (greater than 72 hr) in antiandrogen is lethal. The MCF- cell line contains high-affinity receptors for androgenic steroids demonstrable by sucrose density gradients and competitive protein binding analysis. By cross-competition studies, androgen receptors are distinguishable from estrogen receptors also found in this cell line. Concentrations of steroid that saturate androgen receptor sites in vitro are about 1000 times lower than concentrations that maximally stimulate the cells. Changes in quantity and affinity of androgen binding to intact cells at 37 degrees as compared with usual binding techniques using cytosol preparation at 0 degrees do not explain this difference between dissociation of binding and effect. However, this difference can be explained by conversion of [3H]-5alpha-dihydrotestosterone to 5alpha-androstanediol and more polar metabolites at 37 degrees. An examination of incubation media, cytoplasmic extracts and crude nuclear pellets reveals probable conversion of [3H]testosterone to [3H]-5alpha-dihydrotestosterone. Our data provide compelling evidence that some human breast cancer, at least in vitro, may be androgen dependent.

Androgen Antagonists↗
PubMed1976

Interactions of antiestrogens with human breast cancer in long-term tissue culture.

A variety of antiestrogens can be shown to antagonize estrogen action in animal model systems. Several of these compounds are useful in the management of metastatic human breast cancer. To further elucidate their mechanism of action, we studied several of these compounds using human breast cancer cell lines maintained in long-term tissue culture as a model system. Antiestrogens including tamoxifen (NSC-180973; ICI-46474), nafoxidine. CI-628, and clomiphene citrate inhibit macromolecular synthesis below control levels in two human breast cell lines. This effect is limited to cell lines which contain estrogen receptors. Simultaneous addition of as little as 1000-fold less estradiol prevents antiestrogen effects. Sequential addition of estrogen for up to 48 hours to cells incubated in antiestrogen reverses inhibition. If cells are continued in antiestrogen alone for more than about 3 days, inhibitory effects become irreversible. The cells detach from the surface of the culture vessel and are no longer viable. Tamoxifen competes with 3H-estradiol for specific receptor sites but with about a 100-fold lower apparent affinity. Direct binding of 3H-tamoxifen and 3H-estradiol to duplicate cytoplasmic extracts reveals equivalent numbers of binding sites but a 20-fold lower affinity for the antiestrogen. There is reasonable agreement between concentrations of tamoxifen which bind to receptor and concentrations which inhibit cells.

Animals↗
PubMed1976

Therapeutic use of tamoxifen in advanced breast cancer: correlation with biochemical parameters.

Tamoxifen (NSC-180973; ICI-46474) can provide palliation to patients with advanced breast cancer whose tumors contain estrogen-binding proteins (EBP). The drug is most effective in patients with bone metastasis and minimal prior therapy. In the present study, 72 patients with advanced breast cancer were evaluated for their response to oral tamoxifen therapy administered at a dose of 20 mg twice daily. Twenty-eight of 72 patients (38%) demonstrated objective responses to tamoxifen therapy. For patients with a positive EBP and no prior chemotherapy, eight of 11 (74%) responded. No patient possessing a tumor negative for EBP achieved a remission. Patients with tumors that possessed normal arylsulfatase B and glucose-6-phosphate dehydrogenase enzyme activities responded most favorably to tamoxifen therapy. These results demonstrate that tamoxifen is effective in the treatment of patients with advanced breast cancer, and EBP and specific enzymes might be useful in selecting the patients for hormone manipulation.

Adult↗