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Biomedical subjects

M E Lippman

Publications and source records attributed to M E Lippman.

At least 271 records · Page 15Linked to original sources
PubMed1982

Specific cytotoxicity of 16 alpha-[125I]iodoestradiol for estrogen receptor-containing breast cancer cells.

We attempted to induce specific killing of estrogen receptor-containing breast cancer cells using estradiol coupled to a high specific activity gamma emitting isotope of iodine. MCF-7 human breast cancer cells were incubated with 16 alpha-[125I]iodoestradiol alone ([125I]E2), or with 16 alpha-[125I]iodoestradiol plus 100-fold excess 17 beta-estradiol (E2), and then viably frozen. After 8 weeks, the [125I]E2 exposed cells and the [125 I]E2 plus E2 exposed cells were 10% and 77% of controls, respectively. When the breast cancer cell line MDA-MB-231 which does not contain estrogen receptors was used, the rate of cell death was similar to the competed MCF-7 cells. When specific cytotoxicity was compared using a cloning technique, nearly a 5 log reduction in surviving cell fraction was seen with [125I]E2, as compared to identical cells treated with [125I]E2 plus competitor. This technique shows promise for selecting a population of cells with defects in their estrogen receptor and in studying subcellular hormone interactions.

Breast Neoplasms↗
PubMed1982

Phase II trial of chlorozotocin in malignant melanoma, breast cancer, and other solid tumors.

We have conducted a broad phase II clinical trial of chlorozotocin in 74 patients including 28 with malignant melanoma, 18 with breast cancer, nine with non-Hodgkin's lymphoma, six with nonseminomatous testicular cancer, five with ovarian cancer, four with sarcoma, three with non-beta islet cell carcinoma of the pancreas, and one with anaplastic carcinoma of the thyroid. Objective responses were noted only in 15% of the patients with melanoma and in 11% of the patients with non-Hodgkin's lymphoma. Significant leukopenia and thrombocytopenia were observed only in previously treated patients. Chlorozotocin does not appear to offer clinically significant advantages over other currently available nitrosoureas.

Adolescent↗
PubMed1982

Vasopressin: action on WRK-1 rat mammary tumor cells.

WRK-1, a cell line in long-term culture derived from a 7, 12-dimethylbenz[a]anthracene-induced rat mammary tumor, responds to physiologic concentrations of vasopressin with increased precursor incorporation into phospholipids and with increased protein accumulation. Because vasopressin has been reported to be a potent mitogen for Hela cells and 3T3 cells, a study was conducted to determine whether it could act as a mitogen for WRK-1 cells. Under no conditions was a clear-cut mitogen response to vasopressin demonstrated.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Pharmacology of 13-cis-retinoic acid in humans.

Vitamin A and its analogs (retinoids) have shown great promise for the chemoprevention of cancer as well as being a possible new class of chemotherapeutic agents. A Phase I and II trial of 13-cis-retinoic acid in advanced cancers was initiated, and the clinical pharmacology of the drug was studied. All patients received p.o. 13-cis-retinoic acid starting at 0.5 mg/kg/day, escalating over 4 weeks to a maximum dose of 8 mg/kg/day in divided doses. Although there was a linear correlation of plasma concentration with dose escalation, large inter-individual variations in peak plasma concentrations were noted. At the maximum drug dose, the mean peak plasma concentration was 4 X 10(-6) M. There was little drug accumulation on this schedule, as trough concentrations between p.o. doses often dropped below 1 X 10(-6) M. The drug was metabolized extensively to a metabolite, the concentrations of which exceeding parent 13-cis-retinoic acid concentrations with chronic dosing. Retinol concentrations were below the normal range.

Administration, Oral↗
PubMed1982

Hormonal regulation of net DNA synthesis in MCF-7 human breast cancer cells in tissue culture.

Estrogens and anti-estrogens have striking effects on growth of target tissues in vivo. In order to examine these effects in vitro, experimental methods for the rigorous assessment of rates of net DNA synthesis in tissue culture systems are required. The quantitation of DNA synthesis with inorganic [32P]orthophosphate is described. The limitations of more conventional [3H]thymidine labeling are illustrated in this hormonally responsive system. Estrogen administration increases the specific activity of acid-soluble phosphate and increases net DNA synthesis relative to controls in MCF-7 human breast cancer cells. Stimulation is most evident after 36 hr of hormone treatment. Conversely, tamoxifen produces substantial inhibition of net DNA synthesis after 36 hr of hormone treatment. Thymidine availability modulates the effect of estrogens and anti-estrogens on DNA synthesis and constitutes an independent experimental variable.

Breast Neoplasms↗
PubMed1981

Estradiol-independent growth of a subline of MCF-7 human breast cancer cells in culture.

An estrogen-independent variant (R3) was selected by cloning wild type MCF-7 cells in soft agar in the presence of tamoxifen. R3 has a slightly slower growth rate under optimal growth conditions. Estradiol and tamoxifen have minimal effects on growth rate and thymidine incorporation as compared to wild type MCF-7 cells. R3 contains both cytoplasmic receptor and a receptor derived from crude nuclear extract with slightly higher numbers of cytosol receptor than wild type MCF-7. The same dissociation constant (Kd) and the same molecular weight (estimated by Sephadex chromatography) and sucrose density behavior for both cytoplasmic and nuclear estrogen receptor are seen in R3 and MCF-7. Estrogen receptor complexes were activated by salt and nucleotide and translocated to the nucleus equivalently in R3 and MCF-7. Relative binding affinities and extent of competition by estradiol and tamoxifen for cytoplasmic estrogen receptor are the same for MCF-7 and R3. Induction of progesterone receptor and nuclear estrogen receptor processing following treatment with estradiol in R3 is minimal compared with MCF-7. DNA affinity (as assessed by DNA cellulose chromatography) of estrogen receptor complexes from R3 and MCF-7 is different. R3 appears to represent a cell with a defect expressed in receptor function apart from the initial hormone-binding step.

Breast Neoplasms↗
PubMed1981

Isolation and characterization of a tamoxifen-resistant cell line derived from MCF-7 human breast cancer cells.

A tamoxifen-resistant variant (R27) was selected by cloning wild type MCF-7 cells. R27 has the same growth rate as MCF-7 under optimal conditions. But tamoxifen has no effect on the growth rate (growth constant of R27 under control condition, 0.071 +/- 0.007 day-1; tamoxifen-treated cells, 0.073 +/- 0.011 day-1) and minimal effects on thymidine incorporation in R27, whereas tamoxifen has a strongly suppressive effect on the growth rate and thymidine incorporation in MCF-7. The estradiol-mediated stimulation of growth in R27 is somewhat less than in MCF-7 (growth constants of R27 and MCF-7 are 0.112 +/- 0.015 and 0.125 +/- 0.009 day-1, respectively. R27 contains unoccupied receptors in both cytoplasmic and crude nuclear extract fractions with slightly higher numbers of cytosol receptors than wild type MCF-7. The same dissociation constant and the same molecular weight estimated by Sephadex chromatography and the same sucrose density behavior were observed in R27 and MCF-7. Extent of competition with estradiol and tamoxifen for cytoplasmic estrogen receptor is the same for R27 and MCF-7. Induction of progesterone receptor following treatment with estradiol is the same for R27 and MCF-7. Estrogen receptor is activated by salt and nucleotide in both MCF-7 and R27; however, the extent of activation is much higher in MCF-7 than R27.

Breast Neoplasms↗
PubMed1981

Specific estrogen receptor binding and biological effects of 16 alpha-iodoestradiol on human breast cancer cells.

16 alpha-Iodoestradiol was evaluated as an estrogen in MCF-7 and ZR-75-1 human breast cancer cells. 16 alpha-[125I]Iodoestradiol binds to equivalent numbers of specific estrogen receptors with a comparable binding affinity and similar sucrose density gradient behavior. 16 alpha-Iodoestradiol translocates receptor sites to the nucleus and induces a full range of estrogenic effects including thymidine incorporation, cell growth, and progesterone receptor. Because of its high specific activity, this compound may have unique applications on imaging of estrogen receptor-containing cells and specific receptor-mediated cytotoxicity.

Breast Neoplasms↗
PubMed1981

Purification and properties of estrogen-responsive cytoplasmic thymidine kinase from human breast cancer.

The effect of 17 beta-estradiol on cytoplasmic thymidine kinase activity was studied in MCF-7, a human breast cancer cell line in culture which responds to estrogens with an increase in the rate of growth. Levels of 17 beta-estradiol which maximally stimulate [3H]thymidine incorporation into DNA also maximally stimulate thymidine kinase activity. The Vmax for thymidine increased while the Km was not affected by estrogen stimulation when performed on nonpurified enzyme. Tamoxifen, an antiestrogen, decreased the specific activity of the enzyme. To further study its hormonal regulation, cytoplasmic thymidine kinase was purified greater than 2000-fold by affinity column chromatography. The purified preparation migrated in one band to a pI of 8.5 on an isoelectric focusing gel. The purified thymidine kinase was further characterized by examining its molecular weight, pH optimum, heat stability, utilization of phosphate donors, inhibition by nucleotides, and the effect of pyrimidine nucleoside analogs.

Breast Neoplasms↗
PubMed1980

Quantitative estrogen receptor analyses: the response to endocrine and cytotoxic chemotherapy in human breast cancer and the disease-free interval.

The usefulness of estrogen receptor (ER) analyses was assessed in a variety of clinical situations. The predictive accuracy of the test is substantially increased by quantification. ER analyses accurately predict objective responses to endocrine therapy independently of other clinical prognostic criteria. In addition, ER positivity is associated with a decreased response rate to cytotoxic chemotherapy in patients with metastatic breast cancer. Finally, the presence of ER is positively associated with a prolonged disease-free interval independent of menopausal status, tumor size, and axillary lymph node involvement.

Adult↗
PubMed1980

The use of immunocytochemical techniques for the detection of steroid hormones in breast cancer cells.

Indirect immunofluorescence and immunoperoxidase assays were developed to detect estradiol and progesterone in breast cancer cells. Appropriate controls were used to confirm immunologic specificity. Studies of estradiol binding by human breast cancer cells identified three groups: no detectable binding (25%); all tumor cells exhibiting binding although to different degrees (4%); and tumors with varying numbers of positive and negative cells (71%). Similar observations were made with respect to progesterone binding. The percentage of cells with estradiol binding was correlated with the amount of estrogen receptors (ER) present in the tumor specimens. Post-hormone binding events e.g., nuclear binding of estradiol, were also evaluated. Some tumor cells showing cytoplasmic binding of estradiol did not show nuclear binding of estradiol; such tumors lacked detectable diethylstilbestrol under routine assay conditions, and relatively high concentrations of estradiol were needed to observe estradiol-specific staining. The results suggest that the immunocytochemical assays detect hormone-specific binding, but that the binding is probably due to multiple classes of steroid-binding sites.

Animals↗
PubMed1980

Neurohypophysial-hormone-responsive cell line derived from a dimethylbenzanthracene-induced rat mammary tumour.

WRK-1, a cloned cell line derived from a rat mammary tumour, responds to physiological concentrations of vasopressin and pharmacological concentrations of oxytocin with increased incorporation of [14C]acetate into lipids and increased protein accumulation. The presence of pharmacological concentrations of insulin, which itself is active on the WRK-1 cells, further enhances the effects of the neurohypophysial hormones. Unlike the action of vasopressin on other responsive tissues, the stimulation of acetate incorporation by WRK-1 cells is not observed until 24 h after the addition of the hormone. The lipids synthesized in response to the hormones are predominantly polar lipids, rather than the triclyclycerold characteristic of the differentiated mammary gland. [1-Deaminocysteine, 8-D-arginine] vasopressin, a vasopressin analogue that lacks pressor activity, has no effect on WRK-1 cells.

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

Changes in multiple or sequential estrogen receptor determinations in breast cancer.

Estrogen receptor (ER) analyses are widely used in the management of patients with breast cancer. Few data are available concerning variations in ER as a function of time and therapy. We examined patients in whom multiple biopsies and receptor analyses were either performed simultaneously or over time with or without intervening chemotherapy or endocrine therapy. In 27 patients with simultaneous assays from different metastatic sites, concordant results were obtained in 23 (85%) with respect to classifying a tumor as ER+ or ER-. In 34 patients, multiple assays were performed over time. The receptor concentrations were concordant in patients receiving no intervening therapy. In 10 patients receiving hormonal therapy, the median receptor concentration changed from 66 femtomoles per mg cytoplasmic protein pretherapy to 8 femtomoles post therapy (P less than 0.05). This change suggested that hormonal therapy selectively eliminates ER+ cells. In 19 patients receiving intervening chemotherapy, the median receptor concentrations pre and post therapy were similar. We conclude that simultaneous assays from multiple metastatic sites are highly concordant and unlikely to change over time without intervening therapy, but marked changes occur following therapy with a decrease in receptor concentration after endocrine therapy.

Antineoplastic Agents↗