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Biomedical subjects

V C Jordan

Publications and source records attributed to V C Jordan.

At least 271 records · Page 15Linked to original sources
PubMed1987

Estrogenic effects of phenolphthalein on human breast cancer cells in vitro.

There is a structural similarity between phenolphthalein and the triphenylethylenes which are known to interact with the estrogen receptor of human breast tissue. Phenolphthalein (10 microM) competed with estrogen for binding to MCF-7 human breast cancer cells in tissue culture and induced the synthesis of the progesterone receptor. The antiestrogen 4-hydroxytamoxifen blocked progesterone receptor induction both by estradiol and by phenolphthalein. Both estradiol (0.1 nM) and phenolphthalein (10 microM) stimulated cell growth as measured by DNA and protein assays. This growth stimulation was blocked by 4-hydroxytamoxifen. Phenolphthalein glucuronide, the major phenolphthalein metabolite, did not inhibit estrogen binding, induce progesterone receptor synthesis, or stimulate MCF-7 cell growth in culture. Yellow phenolphthalein, an impure phenolphthalein preparation used in nonprescription laxative preparations, had similar properties to pure phenolphthalein. Physicians should be aware of the weak estrogenic action of phenolphthalein, especially when recommending laxatives for breast cancer patients with confirmed liver and mesenteric metastases.

Binding, Competitive↗
PubMed1987

Stimulation of breast cancer cells in vitro by the environmental estrogen enterolactone and the phytoestrogen equol.

The phenolic lignans enterolactone and enterodiol appear periodically in women's urine, dependent upon synthesis from plant-derived lignans by the intestinal microflora. The phytoestrogen equol is also present in women's urine, and is also derived from a vegetarian diet. Antiestrogenic or antiproliferative actions of these compounds have been postulated and related to the observation that there is a reduced incidence of breast cancer associated with diet. We evaluated the estrogenic and antiestrogenic activity of these compounds using four sensitive assays in tissue culture, including the use of human breast cancer cell lines T47D and MCF-7. Unexpectedly, we found that enterolactone and enterodiol, as well as equol, are weak estrogens, and that enterolactone and equol could stimulate the growth of estrogen-dependent breast cancer cell lines. We suggest that these environmental agents can promote the growth of breast cancer, particularly hormone-dependent metastases that may be located near the gut or in the mesenteries or liver, where the concentration of these intestinally produced compounds would be highest. Treatment with an antiestrogen such as tamoxifen blocks the estrogenic activity of these compounds. In the absence of treatment with an antiestrogen such as tamoxifen, hormonal therapy to block steroidal estrogen synthesis in a patient with breast cancer could conceivably be circumvented by a vegeterian diet rich in the precursors to estrogenic compounds such as enterolactone and equol.

4-Butyrolactone↗
PubMed1987

Strategies for breast cancer therapy with antiestrogens.

Current clinical research is focused upon the application of adjuvant therapy for the treatment of breast cancer. Combination chemotherapy is the most successful adjuvant therapy for premenopausal patients whereas the antiestrogen tamoxifen (1 or 2 yr) is successful in postmenopausal disease. We have developed a unifying strategy for the treatment of breast cancer. The thesis is based upon the application of continuous adjuvant therapy with tamoxifen in a low estrogen environment. Chemotherapy causes a chemical castration in premenopausal patients. In contrast, tamoxifen causes an increase in steroidogenesis. A combination of both approaches will work against each other until ovarian failure occurs. Patients should be checked for castration to provide a low estrogen environment in which tamoxifen, a competitive antagonist of estrogen action, can effectively work. Laboratory evidence using carcinogen-induced rat mammary tumor models demonstrates the efficacy of long-term therapy. Studies with the human breast cell line MCF-7 grown in athymic mice show that tamoxifen is a tumoristatic agent so that once the therapy is stopped, tumors can be regrown by estrogen administration. Patients should receive continuous tamoxifen therapy to prevent the growth-stimulating effects of adrenal steroids, environmental and phyto-estrogens.

Animals↗
PubMed1987

Adaptation of estrogen-dependent MCF-7 cells to low estrogen (phenol red-free) culture.

When human breast cancer-derived MCF-7 cells were maintained in low estrogen medium (phenol red-free), the cells adapted to grow without added estrogen, but growth could be inhibited by antiestrogen in the medium. Estrogen-stimulated progesterone receptor levels remained basal but could be stimulated by estradiol. Estrogen receptor content increased steadily during adaptation, which may model the increasing levels of estrogen receptor observed in breast cancer with increasing patient age. The mechanism of the adaptation to low estrogen medium is unclear; however, cell lines such as MCF-7 may need to be cultured in the presence of an estrogen such as phenol red in order to maintain a stable estrogen-sensitive phenotype. On the other hand, maintenance of estrogen-dependent cells in low estrogen media may convert them to dependence on factors which are not currently understood. This may ultimately increase their value as models of hormone action.

Cell Division↗
PubMed1987

Zoladex: a sustained-release, monthly luteinizing hormone-releasing hormone analogue for the treatment of advanced prostate cancer.

Zoladex, a sustained-release luteinizing hormone--releasing hormone (LHRH) analogue administered by subcutaneous injection every 28 days, was evaluated at three dose levels in 46 men with untreated advanced prostate cancer. All three Zoladex doses yielded similar endocrinologic effects. After initial transient increases in serum luteinizing hormone, follicle-stimulating hormone, and testosterone concentrations, serum testosterone was suppressed uniformly to castration levels within 22 days. At a median follow-up of 41 weeks, Zoladex had maintained persistent suppression of serum testosterone. Measurements of serum Zoladex levels indicated that release of the drug from the injected depot was sustained over a period of 1 month and that there was no drug accumulation as evaluated over an initial 3-month period. No antibodies to Zoladex were detected. Tumor regression rates and side effects with Zoladex therapy were similar to those reported with daily injections of subcutaneous LHRH therapy. Signs and symptoms consistent with a brief tumor flare after the first injection of the LHRH analogue were noted in eight (17%) of the study entrants. Spinal cord compression was observed in two patients within 1 week from the onset of therapy. Zoladex is considered to be an effective, sustained-release LHRH analogue for the treatment of patients with prostate cancer.

Adenocarcinoma↗
PubMed1987

Laboratory models of breast cancer to aid the elucidation of antiestrogen action.

The historical development of carcinogen-induced rat mammary tumors is reviewed. Most work has been done with the polycyclic hydrocarbon dimethylbenz[a]anthracene (DMBA). Huggins was the first to describe a protocol for the routine production of DMBA-induced mammary tumors and demonstrated their ovarian dependency. Pearson found that DMBA-induced tumors could not grow during estrogen administration in hypophysectomized rats, and it was subsequently shown that estrogen-stimulated prolactin release is responsible for tumor growth. The antiestrogen tamoxifen has been used in the treatment of breast cancer and has been studied extensively in the DMBA-induced rat mammary carcinoma model. The complexities of tamoxifen's pharmacology in vivo suggested that the development of estrogen-responsive systems in vitro might facilitate an understanding of tamoxifen's mode of action. The description of estrogen-stimulated prolactin synthesis by primary culture of pituitary gland cells provided an opportunity to study the structure-activity relationships of antiestrogens. A model ("crocodile model") to describe the interaction of estrogens and antiestrogens is proposed. An estrogen will permit the conformation change in the receptor that is necessary to translate into prolactin synthesis. An antiestrogen wedges into the binding site on the receptor to prevent changes in protein conformation. As a result prolactin synthesis is inhibited. An extensive study of structure-activity relationships has been used to describe the nature of the ligand binding site of the estrogen receptor. The model can be used to predict the pharmacology of new agents.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Species-specific pharmacology of antiestrogens: role of metabolism.

The nonsteroidal antiestrogen tamoxifen exhibits a paradoxical species-specific pharmacology. The drug is a full estrogen in the mouse, a partial estrogen/antiestrogen in humans and the rat, and an antiestrogen in the chick oviduct. Inasmuch as tamoxifen has antiestrogenic effects in vitro, differential metabolism of tamoxifen to estrogens might occur in the species in which it has an estrogenic pharmacology. Tamoxifen or its metabolite 4-hydroxytamoxifen could lose the alkylaminoethane side chain to form the estrogenic compound metabolite E or bisphenol. Sensitive metabolic studies with [3H]tamoxifen in chicks, rats, and mice identified 4-hydroxytamoxifen as the major metabolite, but no potentially estrogenic metabolites were observed. Athymic mice with transplanted human breast tumors can be used to study the ability of tamoxifen to stimulate target tissue or tumor growth. Estradiol caused the growth of transplanted MCF-7 breast cancer cells into solid tumors and a uterotrophic response. However, tamoxifen does not support tumor growth when administered alone, although it stimulates uterine growth. Since a similar profile of metabolites is sequestered in human and mouse tissues, these studies strongly support the concept that the drug can selectively stimulate or inhibit events in the target tissues of different species without metabolic intervention.

Animals↗
PubMed1986

Effects of antiestrogens on the induction of vitellogenin and its mRNA in Xenopus laevis.

The egg yolk protein precursor vitellogenin is induced by estrogen in the liver of male Xenopus laevis. The large rise in serum vitellogenin is accompanied by a corresponding increase in intracellular levels of vitellogenin and its mRNA. In the present study this model system was used to examine the subcellular sites of action of triphenylethylene antiestrogens (e.g. tamoxifen). Tamoxifen was extensively metabolized to 4-hydroxytamoxifen in Xenopus and both of these antiestrogens were used in this study. Pre-injection with tamoxifen or 4-hydroxytamoxifen suppressed the estrogen-dependent induction of vitellogenin in serum. 4-Hydroxytamoxifen also inhibited the induction of intracellular vitellogenin and its mRNA by estrogen suggesting that this metabolite of tamoxifen is able to inhibit estrogen-induced transcription of the vitellogenin genes. Neither tamoxifen nor 4-hydroxytamoxifen stimulated the production of serum vitellogenin as assayed by a sensitive dot immunoblot assay. However either compound alone induced low amounts of vitellogenin mRNA and stimulated the production of intracellular vitellogenin to levels 10-40% of those produced by similar doses of estradiol. Since 10-40% of the serum levels of vitellogenin produced by estradiol would have been detected by the dot immunoblot assay, these data suggest that antiestrogens may have effects on post-translational processing or secretion of vitellogenin in addition to their effects on vitellogenin transcription.

Animals↗
PubMed1986

Oestrogenic and antioestrogenic actions in a series of triphenylbut-1-enes: modulation of prolactin synthesis in vitro.

The oestrogenic and antioestrogenic activities of a series of substituted derivatives of 1,1,2 triphenylbut-1-ene have been determined using primary cultures of rat pituitary gland cells to monitor prolactin synthesis in vitro. The relative binding affinity of the agonists for the oestrogen receptor was consistent with their oestrogenic potency. Bis para substitution at C1 of 1,1,2 triphenylbut-1-ene with either phenolic or acetoxy groups produced partial agonists. The antioestrogenic properties were reversible by the incubation of cells with increasing concentrations of oestradiol. The results lend support to a hypothetical single binding site model of oestrogen action, based upon an adaptation of Belleau's macromolecular perturbation theory.

Alkenes↗
PubMed1986

Determination of estrogen receptor in breast cancer using monoclonal antibody technology: results of a multicenter study in the United States.

Three laboratories compared their routine steroid binding assays with the Abbott estrogen receptor-enzyme immunoassay (ER-EIA) to determine ER in breast cancer cytosols. Each laboratory was first trained to use the ER-EIA kit and then performed routine proficiency panels to determine assay reproducibility. The frozen panels prepared from MCF-7 cytosol produced good intraassay results but the between assay coefficients of variation were frequently above 10%. Lyophilized MCF-7 cytosols produced better reproducibility upon repeated assay. One laboratory demonstrated that New England Nuclear steroid binding kits and the ER-EIA produced comparable results when MCF-7 lyophilized cytosols were used. The analysis of breast tumor samples demonstrated excellent linear correlation coefficients for each laboratory (greater than 0.92 N approx. 60 samples each) but different slopes. The comparison of the ER-EIA with the New England Nuclear steroid binding assay produced a slope of 1.13. The ER-EIA appears to produce comparable results to the conventional steroid binding assays for the determination of ER in breast tumor cytosols.

Antibodies, Monoclonal↗
PubMed1985

Metabolism of tamoxifen and its uterotrophic activity.

Tamoxifen is an estrogen agonist in mouse uterus, a partial estrogen agonist/antagonist in rat uterus, and a pure estrogen antagonist in chicken oviduct. Tamoxifen metabolism was examined both in vitro and in vivo to determine if differences in the species response to this drug resulted from the differential formation of metabolites with estrogenic or antiestrogenic activity. Animals were given a subcutaneous injection of [3H]tamoxifen, and 4 or 24 hr later tamoxifen and its metabolites were extracted from tissues and separated by TLC. The profiles of metabolites extracted from the livers of these species were qualitatively similar; the principle metabolite was 4-hydroxytamoxifen, which comprised 27, 14, and 16% of the radioactivity from mouse, rat, and chicken livers, respectively, at 24 hr. Tamoxifen, however, was the principal compound extracted from all three livers. Metabolites extracted from mouse and rat uteri were the same ones obtained from liver, although their abundance (relative to tamoxifen) was much lower in uteri than in liver. Metabolite E and bisphenol, two tamoxifen derivatives that we believed might account for the uterotrophic effect of tamoxifen in the mouse, were found not to be formed in either liver or uterus. Tamoxifen metabolism was also studied in vitro using liver microsomes from these same species; The same metabolites were formed in vitro as in vivo, although their relative abundances were lower in vitro. No clear-cut differences in metabolism were seen that would account for the disparate pharmacological effects of tamoxifen in these species.

Animals↗
PubMed1985

Possible mechanisms for the agonist actions of tamoxifen and the antagonist actions of MER-25 (ethamoxytriphetol) in the mouse uterus.

Experiments were conducted to determine why tamoxifen, a non-steroidal antiestrogen, is uterotrophic in mice, whereas MER-25 (ethamoxytriphetol), a structurally related compound, is antiuterotrophic. Initial experiments indicated that the pituitary was not required for a uterotrophic response in mice to either estradiol (E2), tamoxifen (TAM), or 4-hydroxytamoxifen (4-OH-TAM) MER-25 was not uterotrophic in mice but was capable of completely inhibiting the uterotrophic responses of mice to estrogens (E2) as well as antiestrogens (TAM and 4-OH-TAM); this inhibition was reversible by increasing the dose of the antiestrogen (TAM). The relative binding affinities (RBA) of TAM, 4-OH-TAM, and MER-25 to mouse uterus estrogen receptor (ER) and mouse liver antiestrogen binding sites (AEBS) were compared to determine whether either (or both) of these sites mediate the biological effects of these compounds. E2 is arbitrarily assigned an RBA of 100 for ER; similarly, TAM is assigned an RBA of 100 for AEBS. MER-25 bound to AEBS with an RBA of 8.9 and to ER with an RBA of less than 0.06; in contrast, TAM and 4-OH-TAM bound to AEBS with RBAs of 100 and 53, respectively, and to ER with RBAs of 2 and 131, respectively. Five other compounds that had similar RBAs as MER-25 for AEBs (RBAs in the range 4-9) and for ER (RBAs less than 0.06) were tested for their antiuterotrophic activities in vivo against both estrogen (E2) and antiestrogen (TAM) in ovariectomized mice. None of these compounds were antiuterotrophic against either estradiol or tamoxifen (P less than 0.01), nor were any of the compounds uterotrophic in mice. These data suggest that differences in the biological actions of tamoxifen and MER-25 in mice are not mediated through AEBS and are most likely due to differences in their interactions with ER.

Animals↗
PubMed1985

Rat uterine growth and induction of progesterone receptor without estrogen receptor translocation.

The rat uterus responds to estradiol (E2) and E2 benzoate stimulation with an increase in progesterone receptor production and with growth. These responses were also elicited to varying degrees by a series of estrogenic (ICI 77,949 and ICI 47,699) and antiestrogenic triphenylethylene derivatives [tamoxifen (TAM), 4-hydroxy-TAM (4-OH-TAM), and 4-CH3-TAM]. These compounds have a range of affinities for the estrogen receptor (ER) and are able to compete with [3H]E2 binding in the uterus in vivo. Within 1-2 h of a sc injection of high affinity ligands (E2, E2B, and 4-OH-TAM), there was decrease in cytosol ER. This decrease was also observed with TAM, which is metabolized to 4-OH-TAM in vivo. In contrast, there was no decrease in cytosolic ER in animals treated with low affinity compounds (ICI 77,949, ICI 47,699, and 4-CH3-TAM) at any time before the onset of an estrogenic response. Furthermore, the nuclear ER increased after administration of a high affinity ligand (E2), as measured by exchange assay, but no increase in nuclear ER was observed after administration of low affinity ligands (ICI 77,949 and 4-CH3-TAM), although estrogenic responses were produced. From these data we have suggested a functional model to explain ER-mediated events in the rat uterus that supports the recent proposal that unoccupied ER is located in the nuclear compartment. In this model, the majority of unoccupied ER may reside in the nucleus in vivo; however, when the cells are disrupted in vitro, the unoccupied receptor or dissociation of low affinity ligand-ER complex causes unoccupied receptor to fall out of the nucleus and be incorporated into the cytosolic fraction. The high affinity ligand-ER complexes are retained in the nucleus. This would suggest that the apparent translocation of the ER from the cytoplasm to the nucleus may be an artifact. The data may reflect differential extraction of unoccupied receptors from the nucleus rather than transfer of receptor complexes to the nucleus.

Animals↗