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V C Jordan

Publications and source records attributed to V C Jordan.

At least 253 records · Page 14Linked to original sources
PubMed1988

Metabolism of steroid-modifying anticancer agents.

The application of steroid-modifying drugs as a strategy for the treatment of hormone-dependent cancers has gained increasing popularity during the past decade. However, it is important to point out and emphasize that very few of the agents were originally designed for their current application. Most were designed for other purposes, predominantly fertility control (e.g. LHRH agonists and the antiestrogens). Nevertheless, now it is possible to integrate their actions to design rational therapies. There are many reasons for the current interest in antisteroidal drugs. The initial euphoria over the potential ability of combination chemotherapy to cure breast and prostatic carcinoma has proved to be premature. Combination chemotherapy has many severe side-effects which limits patient acceptability, especially if the patient realizes that the likelihood of a cure is remote. In the main, antisteroidal therapies do not have many side-effects and those that do, e.g. aminoglutethimide, are the focus of increased efforts in drug design to produce increased drug specificity. Finally, there is a growing realization that hormone-dependent cancer control with a nontoxic, antisteroidal therapy may be the most acceptable approach currently available for early disease management. Chemotherapy would then be reserved as the final option for treatment. The description of drug metabolism has been central to the development of synthetic LHRH analogs and an understanding of the mode of action of nonsteroidal antiestrogens and antiandrogens. The discovery of steroid synthetic pathways has been essential for the development of the aromatase inhibitors. This whole area of endeavor has now become a major focus of attention for the medicinal chemist. A new generation of agents is entering clinical evaluation which will provide a wealth of valuable information about the successful (or unsuccessful?) methods to control hormone-dependent disease. Since the success or failure of a drug can often depend upon formulation, pharmacokinetics, bioavailability or metabolism, it is our hope that this overview might help solve some of the future problems.

Amino Acid Sequence↗
PubMed1988

Antitumor actions of toremifene in the 7,12-dimethylbenzanthracene (DMBA)-induced rat mammary tumor model.

Toremifene (200 and 800 micrograms/day) or tamoxifen (200 micrograms) were effective in preventing the development of 7,12-dimethylbenzanthracene-induced rat mammary tumors when given p.o. from day 28 after carcinogen administration. This antitumor action was completely reversed if the toremifene or tamoxifen treatment was stopped or partially reversed by coadministration of progesterone (4 mg/day). Large doses of toremifene (4000 and 8000 micrograms/day) for 10 days produced very high circulating levels of the parent compound (282 +/- 49 and 1002 +/- 224 ng/ml, respectively) and N-desmethyltoremifene (2631 +/- 449 and 6999 +/- 1308 ng/ml, respectively). However, even these very high levels did not reduce the number of animals ultimately developing tumors or the number of tumors each animal developed following cessation of toremifene administration. These findings indicate toremifene has a tumoristatic rather than tumoricidal action in this tumor model.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Estrogenic activity of phenol red.

It has recently been reported that phenol red, a pH indicator present in most tissue culture media, is a weak estrogen that can stimulate some estrogen-sensitive cells. However, the relative impact of phenol red on various cell lines is controversial. We examined the effect of phenol red on several estrogen-responsive cell systems that we use to study estrogen action. These included estrogenic stimulation of progesterone receptor and growth in human breast cancer-derived MCF-7 cells, stimulation of growth in human breast cancer-derived T47D cells, stimulation of prolactin synthesis in primary cultures of immature rat pituitary cells, and stimulation of progesterone receptor in primary cultures of immature rat uterine cells. Estrogenic responses in MCF-7 cells were the most sensitive to the presence of phenol red, while the other three cell cultures showed lesser effects of the indicator. In addition to intrinsic differences in cell responses, there were several other factors involved. These included differences in the estrogenic activity of phenol red-containing media and phenol red itself from different commercial suppliers, and differences in the concentration of free phenol red in final media due to binding of the indicator by serum. Higher concentrations of serum reduced the impact of phenol red on estrogenic responses in primary pituitary cells. Phenol red added to rat uterine cytosol competed with estradiol for binding to the estrogen receptor (relative binding affinity (RBA) approx. 0.001), and the acidic and basic forms of the indicator showed similar activity. Some commercial phenol red samples inhibited cell growth at levels of 100 mg/l; these effects were toxic rather than antiestrogenic, because growth inhibition could not be competitively reversed by an excess of estradiol. The amount of the indicator bound to serum in the final media, the source of the phenol red and the sensitivity of different cell types to the indicator ultimately determine its influence to the response of cells in tissue culture.

Animals↗
PubMed1988

Nonisomerizable analogues of (Z)- and (E)-4-hydroxytamoxifen. Synthesis and endocrinological properties of substituted diphenylbenzocycloheptenes.

Substituted 8,9-diphenyl-6,7-dihydro-5H-benzocycloheptenes 6-8, which are ring-fused analogues of (Z)-trans-4-hydroxytamoxifen, (E)-cis-tamoxifen, and (E)-cis-4-hydroxytamoxifen, were synthesized from 7-methoxy-1-benzosuberone. The hydroxy compounds 6 and 8 were individually prepared via a common synthetic intermediate from which either the perfluoro-p-tolyl or the methyl ether functions could be cleaved specifically. Compounds were assayed for binding affinity to estrogen receptors in cytosol and in MCF-7 whole cells and for growth inhibition of MCF-7 cells in vitro and rat uteri in vivo. The endocrinological properties of the cyclic analogues 5-7 paralleled those of the corresponding derivatives of tamoxifen although in the MCF-7 assay 6 was slightly less effective than 4-hydroxytamoxifen at 10(-6) and 10(-7) M. The compound 8 analogues to cis-4-hydroxytamoxifen antagonized the growth stimulation by estradiol of MCF-7 cell or rat uterus growth, and it is therefore an antiestrogen, but its potency was somewhat less, both as an antiestrogen and an estrogen, than reported for cis-4-hydroxytamoxifen attributable to modification of the biochemical properties of the latter by isomerization to the more potent trans isomer. Curiously, in the absence of estradiol, compound 8 stimulated MCF-7 cell growth at low concentration (10(-8) M) but inhibited growth at higher concentration. In contrast, compound 7, which lacked the hydroxy function, was a full estrogen in the rat uterine growth assay. These compounds should be ideal for further structure-activity studies of triarylethylene-based antiestrogens without complications caused by isomerization.

Animals↗
PubMed1988

Oestrogen pre-treatment abolishes luteinising hormone-releasing hormone testosterone stimulation.

In patients with histologically confirmed prostate cancer, oestrogen priming with diethylstilboestrol (DES) (3 mg/day) for 4 weeks prior to the first injection of the LHRH agonist Zoladex (3.6 mg depot form) prevented any rise in the serum testosterone concentration. In contrast, in the groups pre-treated with DES, the first, but not subsequent, injections with Zoladex were associated with a marked surge in luteinising hormone. Treatment with DES beyond the time of the first administration of Zoladex did not provide further endocrinological advantage. Oestrogen priming for 1 month prior to treatment with Zoladex may prevent an exacerbation of signs and symptoms of prostate cancer.

Buserelin↗
PubMed1988

Ligand interaction at the estrogen receptor to program antiestrogen action: a study with nonsteroidal compounds in vitro.

The estrogenic and antiestrogenic actions of the geometric isomers of tamoxifen and 4-hydroxytamoxifen were determined in a PRL synthesis assay using primary cultures of dispersed immature rat pituitary gland cells. 4-Hydroxytamoxifen was 100 times more potent as an antiestrogen than tamoxifen. The cis isomer of tamoxifen was a weak estrogen, but the cis isomer of 4-hydroxytamoxifen was converted to the trans isomer during the 6-day assay. This made an accurate determination of the properties of cis-(E)4-hydroxytamoxifen impossible. A series of fixed ring derivatives of the compounds were evaluated in the PRL synthesis assay in vitro to determine their estrogenic and antiestrogenic activities. The fixed ring derivatives of tamoxifen, cis-tamoxifen and trans-(Z)4-hydroxytamoxifen all had properties that were the same as those of the original triphenylethylenes. The fixed ring derivative of the cis-(E) isomer of 4-hydroxytamoxifen was a weak competitive antagonist of estrogen action with only very slight estrogenic properties. This contrasted with the other cis isomers of triphenylethylenes. We propose that the hydroxyl group on the molecule may orient the ligand at the binding site of the estrogen receptor to place the alkylaminoethoxy side-chain in a position to produce antiestrogen action.

Animals↗
PubMed1988

Estrogen receptor distribution in enucleated breast cancer cell lines.

The intracellular location of estrogen receptors in hormone-responsive cells has been studied with a number of techniques which indicate that the unoccupied receptors are nuclear and not cytoplasmic proteins. We used cell enucleation of two human breast cancer-derived cell lines, MCF-7 and T47D, to determine whether the unoccupied receptors were also nuclear in these cells and to determine whether the weak estrogen phenol red, present in nearly all tissue culture media, affected the distribution of the receptors seen with this technique. Nucleoplasts prepared from the breast cancer cells contained most of the estrogen receptors that were present in whole cells. The cytoplast fraction, which contained some contaminating whole cells, also contained some receptors. However, incubating cells with estradiol before enucleation did not translocate any receptors out of the cytoplast fraction (to the nucleoplasts). The unoccupied receptors appeared to be almost exclusively nuclear in these cells. The same results were obtained with either radioligand binding or enzyme-linked immunoassay used to measure estrogen receptor, and the distribution of receptors was unaffected by the presence of the pH indicator phenol red. In addition, we observed changes in the estrogen receptor content of incubated cytoplasts that were consistent with receptor synthesis, and this may prove to be a useful model system to characterize receptor synthesis and degradation.

Breast Neoplasms↗
PubMed1988

Hormone receptor assays: clinical usefulness in the management of carcinoma of the breast.

The revision of the subcellular model of hormone action is described, with an incorporation of potential autocrine mechanisms. A general overview of available assay methodologies considers the major disadvantages of earlier methods and describes in detail the current methodologies (sucrose gradient analysis, dextran-coated charcoal assays, ER-EIA, ERICA). A major concern with clinical correlations of response to hormone receptor levels is the quality assurance of the multicentric programs. Results from national and international programs are considered. The clinical correlations are divided into four major categories: (1) the response to hormone deprivation (oophorectomy or adrenalectomy), (2) the development of specific agents which exploit receptor mechanisms (antiestrogens) or inhibit steroid biosynthesis (aminoglutehimide), (3) the rates of recurrence of tumors following mastectomy, and (4) the correlation of hormone receptors with current adjuvant therapies.

Breast Neoplasms↗
PubMed1988

Antiestrogen therapy for breast cancer: current strategies and future prospects.

The antiestrogen tamoxifen has had an enormous impact upon the therapy of breast cancer. It is the most widely used antihormonal therapy. The success of tamoxifen has stimulated broader applications of the drug (long-term adjuvant therapy and chemosuppression) and has spurred the development of toremifene, droloxifene, and zindoxifene. However, the clinical evaluation of tamoxifen as a chemosuppressive agent is not sufficiently advanced to be able to provide any conclusion about the success of this strategy. It may be a decade before a randomized clinical study can be analyzed and the value of chemosuppression assessed. In the near future, the clinical evaluation of new antiestrogens will provide additional information about the potential value of these drugs and will perhaps challenge our ideas about the mode of action of antiestrogens as antitumor agents.

Breast Neoplasms↗
PubMed1988

Role of tamoxifen in the long-term treatment and prevention of breast cancer.

The past twenty years have witnessed the introduction and development of antiestrogens as powerful new nontoxic drugs for the treatment of breast cancer. Tamoxifen is currently the agent of choice for the endocrine treatment of breast cancer. Several clinical studies now support the concept that long-term or indefinite adjuvant tamoxifen therapy is of benefit to at least some groups of Stage I/II breast cancer patients (usually those who are estrogen receptor positive). This article will consider the basic laboratory principles that led to the successful clinical testing of long-term adjuvant tamoxifen therapy; future strategies to improve the encouraging early results of long-term antiestrogen therapy will be offered and the use of antiestrogens as a possible preventive in women at high risk for breast cancer will be considered.

Adult↗
PubMed1988

Long-term tamoxifen therapy to control or to prevent breast cancer: laboratory concept to clinical trials.

The successful evaluation of tamoxifen as an antiestrogenic therapy for advanced breast cancer in the early 1970's, has resulted in its availability in more than 70 countries around the world. Currently the drug development process is focusing attention upon long-term adjuvant therapy and the future prospect of chemosuppression. Progress at this stage, however, must be cautious. Trials conducted using women with stage I disease have a high proportion of women who may never have a recurrence. At this point, the risk is justified because the toxicity of tamoxifen is low and disease recurrence is invariably very difficult or impossible to control. Future studies in the general population must be carefully weighed to ensure that the hazards do not exceed the benefits. The pharmacology of tamoxifen seems to be a balance of estrogenic and antiestrogenic effects. Longer treatments with the drug must be carefully monitored. Uterine tissue should be examined to ensure that excessive stimulation does not occur. This is particularly true in the light of the recent report that a human uterine carcinoma, transplanted into athymic mice, can grow more rapidly during tamoxifen therapy (Satyaswaroop et al., 1984; Clark and Satyaswaroop, 1985). In fact, we have recently confirmed this observation in a collaborative study with Dr. Satyaswaroop. We have demonstrated that when athymic mice are transplanted in one axilla with an MCF-7 breast tumor and the human endometrial tumor in the other, tamoxifen causes the endometrial tumor to grow, but not the breast tumor. This again illustrates the target site specific effects of tamoxifen. If, in the long run, the estrogenic side effects of tamoxifen are too severe then there is a case for the development of a non-estrogenic antiestrogen. Clearly this may provide benefit for short term (1-2 years) therapy and avoid any estrogen-like stimulation of tumor growth. Similarly, the concern about antithrombin III depression will be avoided. On the negative side, however, the concerns about atherosclerosis and osteoporosis will again have to be addressed with a new generation of agents.

Animals↗
PubMed1987

Reversal of the antitumor effects of tamoxifen by progesterone in the 7,12-dimethylbenzanthracene-induced rat mammary carcinoma model.

Coadministration of progesterone (4 mg/day) opposed the antitumor activity of tamoxifen (100 micrograms/day) in rats bearing 7,12-dimethylbenzanthracene-induced tumors and also partially prevented the inhibition by tamoxifen (50 micrograms/day started 30 days after 7,12-dimethylbenzanthracene administration) of tumor occurrence even after tamoxifen therapy had been established for 1 or 2 mo. Although prolonged progesterone treatment raised progesterone levels, serum total estrogen levels were not raised above control. The reversal by progesterone of the inhibition of tumor occurrence produced by tamoxifen was blocked by the antiprogestin RU 486. These results demonstrate that progesterone can reverse the tumoristatic action of tamoxifen in the 7,12-dimethylbenzanthracene-induced tumor model and that this may be via a progesterone receptor-mediated mechanism.

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

Long-term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin and antithrombin III.

Plasma levels of luteinizing hormone, sex hormone binding globulin, and antithrombin III were measured in pre- and postmenopausal breast cancer patients receiving adjuvant combination chemotherapy or combination chemotherapy and long-term tamoxifen therapy. The aim was to determine the estrogen-like effects of tamoxifen. The premenopausal patients had received tamoxifen for between 434 and 2592 days and postmenopausal patients between 91 and 1560 days. Tamoxifen caused a consistent rise in sex hormone binding globulin in premenopausal (P less than 0.03) and postmenopausal (P less than 0.01) patients compared to chemotherapy controls. Luteinizing hormone levels were only significantly lowered (P less than 0.008) in premenopausal patients compared to chemotherapy controls. Antithrombin III levels were significantly depressed (P less than 0.001) in postmenopausal patients compared with chemotherapy controls. However, none of the patients had a value that was depressed by more than 30% of the laboratory control (the level of clinical significance). The mean for the group was 90% +/- 4 (mean +/- SD, N = 11). The estrogen-like rise in sex hormone binding globulin produced by adjuvant tamoxifen therapy could be advantageous for maintaining the antiestrogenic action of the drug. A decrease in antithrombin III occurred but was not within a range of clinical concern. We recommend, however, that patients with a history of thromboembolic disorders should be monitored carefully if placed on tamoxifen therapy.

Adult↗
PubMed1987

Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model.

We have compared the antitumor activities of the antiestrogens, keoxifene (LY 156758) and tamoxifen (TAM), using the N-nitrosomethylurea (NMU) rat mammary carcinoma model. To establish an effective antitumor dose of TAM in this model, rats were treated 2 wk after initiation with NMU for 8 wk with s.c. daily injections of 6.25 micrograms, 25 micrograms, or 100 micrograms of TAM in peanut oil. At the 25-micrograms and 100-micrograms daily doses, TAM completely inhibited tumor appearance during the therapy period. An effective antitumor dose of TAM (100 micrograms daily) was compared to 20-, 100-, or 500-micrograms daily doses of keoxifene 7 wk after NMU initiation. None of the keoxifene-treated groups prevented the appearance of tumors as effectively as TAM during 13 wk of therapy. When keoxifene was compared to TAM at equivalent daily doses of 100 and 500 micrograms daily starting 2 wk after NMU injection, the keoxifene groups again failed to prevent the appearance of all tumors during 10 wk of therapy. TAM, however, completely suppressed any tumor formation. In the same experiment, animals treated with 500 micrograms of TAM had therapy stopped after 10 wk, and tumors started to appear 6 wk later. No tumors appeared when animals (n = 25) were treated continuously for 23 wk with 100 micrograms of TAM. In separate experiments, keoxifene (500 micrograms daily) and TAM (500 micrograms and 100 micrograms daily) administered for 1 wk blocked the binding of [3H]-estradiol in NMU tumors and in uteri. The effect lasted for up to 5 wk after antiestrogen therapy was stopped. These experiments demonstrate that keoxifene is not as effective in its antitumor action as TAM in the NMU model.

Animals↗
PubMed1987

Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer.

Ovarian and pituitary hormones were determined in pre- and postmenopausal breast cancer patients before and at intervals during adjuvant chemotherapy or chemotherapy plus tamoxifen (TAM). Chemotherapy did not affect gonadotrophin levels in postmenopausal patients; however, inclusion of TAM in the regimen produced a partial (approximately 50%) reduction in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone. Gonadotrophin levels remained reduced as long as TAM therapy continued, at which time they rose to postmenopausal values. Chemotherapy (6-12 months) caused ovarian failure in premenopausal patients with decreases in estrogen (estrone plus estradiol) and rises in gonadotrophin levels to postmenopausal levels. Inclusion of TAM in the regimen caused an initial 3-fold rise in peak circulating estrogen levels before ovarian failure (6-9 months of therapy). Some younger patients (approximately 40 years of age) who had a short course (4 months) of chemotherapy plus TAM followed by continuous TAM therapy alone resumed ovulatory menstrual cycles. Estrogen, progesterone, and follicle-stimulating hormone levels were increased compared with control subjects. Those patients who experienced ovarian failure with adjuvant chemotherapy plus TAM only had a partial rise in gonadotrophins compared with patients receiving chemotherapy alone. TAM maintained the levels of gonadotrophins for as long as therapy was administered, at which time they rose to postmenopausal levels. Although TAM exhibited estrogen-like effects on gonadotrophins there was no estrogen-like increase in circulating prolactin levels in either pre- or postmenopausal patients. One patient experienced an estrogen receptor-positive recurrence during long-term tamoxifen therapy. Serum levels of tamoxifen and metabolites declined in the year prior to the recurrence and this was associated with a rise in gonadotrophins. This indicated noncompliance by the patient. Compliance can be monitored either directly with serum levels of TAM or by serial gonadotrophin determinations. We suggest that the optimal antitumor activity of TAM will be achieved in a low estrogen environment with continuous high levels of the drug in the serum. We recommend that patients undergoing long-term TAM therapy be monitored for complete ovarian failure and drug compliance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Effects of anti-estrogens on bone in castrated and intact female rats.

The effects of the antiestrogens tamoxifen and keoxifene on the bone density of intact and ovariectomized female rats were determined after 4 months of therapy. The antiestrogens did not cause a decrease in bone density in intact animals, although uterine wet weight did decrease. Ovariectomy caused an increase in body weight (25%) and a significant decrease in femur density (P less than 0.01). Antiestrogens did not further decrease the bone density of ovariectomized rats but rather helped to maintain bone density. Antiestrogens as well as estrogen (oral estradiol benzoate 25 micrograms daily) helped to maintain bone density in the range observed for the intact rats, but inhibited estrogen stimulation of uterine weight. These contrasting pharmacological actions of antiestrogens suggest that patients receiving long-term adjuvant tamoxifen therapy for breast cancer should be evaluated to determine whether tamoxifen can retard the development of osteoporosis.

Animals↗