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Biomedical subjects

V C Jordan

Publications and source records attributed to V C Jordan.

At least 235 records · Page 13Linked to original sources
PubMed1989

Contrasting ability of antiestrogens to inhibit MCF-7 growth stimulated by estradiol or epidermal growth factor.

A potential mechanism is described by which a growth factor may prevent the action of antiestrogens or reactive the growth of hormone-responsive breast carcinoma in patients undergoing tamoxifen (TAM) treatment. Epidermal growth factor (EGF)-stimulated growth (10(-8) M EGF) was assayed in the MCF-7 breast cancer cell line in the presence of various concentrations (10(-10) to 10(-6) M) of three antiestrogens, 4-hydroxytamoxifen (OH TAM), TAM and ICI 164384. In each case, the EGF-stimulated increases in DNA were not inhibited by the antiestrogen. OH TAM and ICI 164384 inhibited estradiol (E2) stimulated cell proliferation in a dose-related fashion. However, in the presence of both E2 and EGF, these two antiestrogens inhibited E2 effects only; EGF promotion of growth was unaffected. Pretreatment of MCF-7 cells for 2 days with either OH TAM or ICI 164384 did not inhibit EGF-induced increases in cell proliferation. We propose that eventual antiestrogen therapeutic failure may be caused by the paracrine influences of growth factors from neighboring cells.

Breast Neoplasms↗
PubMed1989

The paracrine stimulation of MCF-7 cells by MDA-MB-231 cells: possible role in antiestrogen failure.

The influence of paracrine factors secreted by the hormone independent breast cancer cell line MDA-MB-231 on the growth of the hormone dependent breast cancer cell line MCF-7 was examined in the absence of estradiol and in the presence of inhibitory concentrations of antiestrogens. MDA-MB-231 cells were grown on transwell membranes and co-cultured with MCF-7 cells (50,000) plated in 6-well tissue culture dishes. Growth was maximally increased (80%) when MCF-7 cells were grown in the presence of 150,000 or more MDA-MB-231 cells for 4 days. The non-steroidal antiestrogens tamoxifen (10(-10) to 10(-6) M) and 4-hydroxytamoxifen (10(-11) to 10(-7) M), the steroidal antiestrogens ICI 164384 (10(-10) to 10(-6) M) and Ru39411 (10(-11) to 10(-7) M) all inhibited estradiol (10(-11) M) stimulated MCF-7 cell growth in a dose related manner when cultured for 4 days. However, the paracrine stimulation of MCF-7 cells produced by co-culture with 250,000 MDA-MB-231 cells was not inhibited by any of these antiestrogens. These data suggest that in heterogeneous tumors, paracrine factors from hormone independent cells may reverse the growth inhibitory action that antiestrogens have on estrogen-dependent breast cancer cell growth.

Breast Neoplasms↗
PubMed1989

Implications of tamoxifen metabolism in the athymic mouse for the study of antitumor effects upon human breast cancer xenografts.

The metabolism of tamoxifen in the human has been well established and may be important in the antiestrogenic activity of this agent. This study examines whether tamoxifen metabolism in the athymic mouse xenograft model is similar to tamoxifen metabolism in the breast cancer patient. Serum taken from athymic mice 24 h after a single large oral dose (200 mg/kg) of tamoxifen contained compounds corresponding to standards of tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, 4-hydroxy-N-desmethyltamoxifen and tamoxifen-N-oxide when analyzed by high pressure liquid chromatography. The administration of large single doses (200 mg/kg) of 4-hydroxytamoxifen and N-desmethyltamoxifen either alone or in combination produced the expected peaks for the administered agents and a peak confirming the identity of 4-hydroxy-N-desmethyltamoxifen. 4-Hydroxy-N-desmethyltamoxifen was detected in serum from six out of 10 breast cancer patients receiving 10 mg bid of tamoxifen. These patients had tamoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen levels of 108 +/- 23, 2.6 +/- 0.5, and 238 +/- 58 ng/ml, respectively. Repeated large oral doses (200 mg/kg/day for 6 days) of tamoxifen to athymic mice produced a similar array of serum metabolites as seen after the single dose and in the breast cancer patient. However, levels of 4-hydroxytamoxifen (628 +/- 192 ng/ml) were similar to those of tamoxifen (441 +/- 208 ng/ml) whereas N-desmethyltamoxifen (1343 +/- 388 ng/ml) levels were 2-3 times greater. A similar pattern of metabolites was produced with a 50 mg/kg dose of tamoxifen although levels were considerably reduced. Subcutaneous administration of tamoxifen (200 mg/kg/day for 6 days) produced serum levels of the parent compound (120 +/- 19 ng/ml) in the same range as tamoxifen levels in the breast cancer patient. However, although N-desmethyltamoxifen was the major metabolite, levels (115 +/- 18 ng/ml) were only equivalent to those of tamoxifen itself and 4-hydroxytamoxifen levels (26 +/- 5 ng/ml) were appreciably higher than the breast cancer patient. Lowering the dose of tamoxifen (50 mg/kg) administered s.c. produced not only lower circulating tamoxifen levels (41 +/- 3 ng/ml) but also changed the metabolite profile. Rather than N-desmethyltamoxifen levels equivalent to those of tamoxifen, as seen with the higher dose, they were reduced to the level of 4-hydroxytamoxifen (7 +/- ng/ml).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Short- and long-term estrogen deprivation of T47D human breast cancer cells in culture.

The effects of short- and long-term estrogen deprivation on T47D human breast cancer cells was studied. Cells were routinely grown in an estrogenized environment in media containing fetal bovine serum with phenol red indicator. Cells were estrogen deprived (grown in media containing dextran-coated charcoal-stripped fetal bovine serum without phenol red) for either 10 days or at least 8 months, and effects on genotype, receptor content, and cell growth responsiveness were studied. Cells grown in an estrogenized environment are hypertetraploid, whereas long-term estrogen-deprived cells have become hyperdiploid. Short-term estrogen-deprived cells exhibit a decreased growth rate and progesterone receptor (PgR) content, while estrogen receptor (ER) content is not significantly altered. ER mRNA levels are significantly decreased in these cells. Incubation of these cells with estradiol (10(-10) M) for 6 days causes a 5-fold stimulation in cell growth and this stimulation can be inhibited by the antiestrogens 4-hydroxytamoxifen (4-OHT), ICI 164,384, and RU 39411. Cells cultured under long-term estrogen deprivation exhibited an increased growth rate and were refractory to the effects of estradiol and of 4-OHT on cell growth. These cells were ER negative with low levels of PgR; however, one clone of this line was found to be ER and PgR negative. No mRNA for the ER was detected in this line or its clone. With these cell lines it is possible to study the biological characteristics necessary for the outgrowth of a receptor negative, hormone nonresponsive cell population from a receptor positive, hormone-responsive population grown in a estrogen-free environment.

Breast Neoplasms↗
PubMed1989

Laboratory evidence to support the use of long-term adjuvant tamoxifen therapy for breast cancer.

Animal models all demonstrate that tamoxifen is tumouristatic in the case of breast tumours and long-term or indefinite therapy is required to prevent the appearance of tumours. When treatment is stopped, tumours appear spontaneously or can be encouraged to re-appear with oestrogen therapy. These data support the view that adjuvant clinical trials with tamoxifen should employ a 5- or 10-year treatment regimen.

Animals↗
PubMed1989

High-dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects.

High-dose ketoconazole (400 mg orally three times a day) and physiologic replacement doses of glucocorticoids (hydrocortisone, 20 mg 8 AM, 10 mg 4 PM, and 8 PM) were administered to 38 patients with advanced prostatic cancer, refractory to at least initial testicular androgen deprivation. Thirty patients were completely evaluable; six were withdrawn due to possible ketoconazole-related toxicity and were considered drug failures. Two patients were unevaluable due to intercurrent therapy or inability to maintain follow-up. Ketoconazole was generally well tolerated. Mild or moderate nausea and vomiting occurred in 37% of patients, but required dose modification or discontinuation in only three patients; no hepatic damage was seen. Five of 36 patients (14%) responded to ketoconazole as determined by palpable or radiographic tumor mass reduction of 50% or greater and normalization of acid phosphatase or bone scan. Fifty percent of patients entered were stable at 90 days. Plasma androstenedione and dehydroepiandrosterone sulfate (DHEAS) were reduced markedly in almost all patients. Plasma testosterone (T) levels were low and remained unchanged, while gonadotropins were persistently elevated. Mean plasma ketoconazole content was 6.6 micrograms/mL after 28 days of therapy. While ketoconazole with hydrocortisone does suppress plasma androgens in advanced prostatic cancer patients, this infrequently causes regression of cancer that has progressed despite adequate testicular androgen ablation.

Acid Phosphatase↗
PubMed1989

Regulation of prolactin synthesis in vitro by estrogenic and antiestrogenic derivatives of estradiol and estrone.

The estrogenic and antiestrogenic activities of derivatives of estradiol and estrone were determined in vitro using the ability of primary cultures of immature rat pituitary cells to synthesize PRL. Estradiol derivatives were the most potent estrogens in the assay. Large ethinyl substitutions in the 17 alpha position generally caused a decrease in estrogenic potency (up to 1000-fold). The 3 phenolic hydroxyl was important, but not essential, for the estrogenic activity of the estradiol molecule. Estratriene was approximately 1000 times less potent than estradiol. However, significant estrogenic activity was observed with the compound anordin (EC50, 8 x 10(-9) M), which could potentially be converted to a dihydroxylated derivative but without an aromatic A ring. Similarly, the steroid androst-5-ene-3,17-diol was weakly estrogenic (EC50, 3 x 10(-8) M). Steriods with a ketone in the A and D rings were generally inactive as estrogens and antiestrogens. Estradiol derivatives with 17 beta amines were only weak estrogens. Estrone derivatives were less active than the corresponding estradiol derivatives. 4-Nitromethoxyestrone exhibited weak antiestrogenic properties; however, 4-nitroestrone and methoxyestrone were both estrogens. The reason for the antiestrogenic properties of 4-nitromethoxyestrone is obscure, as the compound does not have structural features similar to those of known nonsteroidal antiestrogens. Minor alterations to the estradiol molecule at the 11 beta (OH) or 6 (ketone) position had little effect on estrogenic potency; however, large substitutions at the 11 beta (RU 39,411) or 7 alpha (ICI 164384) position produced antiestrogenic compounds. RU 39,411 was approximately 10 times more active as an antiestrogen than 4-hydroxytamoxifen, whereas ICI 164,384 was approximately 10 times less active than 4-hydroxytamoxifen. A series of hypothetical models is proposed that could explain the antiestrogenic properties of RU 39,411 and ICI 164,384 by an interaction with the estrogen receptor steroid-binding site.

Animals↗
PubMed1988

Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration.

Long-term tamoxifen (TAM) therapy was examined in athymic mice bearing MCF-7 tumors of different sizes. Six months of TAM treatment caused no increase in tumor size (compared to placebo treatment) for animals treated initially following implantation of tumor pieces (approximately 1 mm3) or for animals with 0.2-cm2 tumors (grown with 1 month of estrogen treatment). Tumors could be regrown with estradiol treatment in animals treated with either therapy and these tumors contained both estrogen and progesterone receptors. However, more tumors could be restimulated with estradiol following pretreatment with TAM than with placebo. A third group of animals had larger tumors (grown with 7 weeks of estrogen treatment to a approximately 0.6-cm2 area) before TAM or placebo treatment. These tumors partially regressed after 4 months of TAM or placebo therapy but began to regrow in both groups until the end of the experiment at 8 months. Tumors that grew in both groups were estrogen receptor positive and when retransplanted into athymic animals could grow with estradiol. However, the tumor that grew during TAM therapy, when retransplanted, could grow successfully only with further TAM treatment. Tumors growing with TAM contained double the estrogen receptor content of the estradiol-stimulated MCF-7 tumors that were not exposed to TAM [390 +/- 37 (SE) fmol/mg protein versus 174 +/- 14 fmol/mg protein]. These results may represent a form of TAM resistance, i.e., TAM dependence that may occur before hormone independence is exhibited.

Animals↗
PubMed1988

Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen.

The endocrine status of 49 premenopausal women taking tamoxifen after completion of adjuvant chemotherapy for breast cancer was determined by radioimmunoassay from serial blood samples. Of these 49 women, 7 had regular menses, 14 had irregular menses, 23 were amenorrheic, and 5 had undergone hysterectomies. A group of 12 premenopausal women who had no history of breast cancer and were not taking tamoxifen served as a control group. Evidence of ovarian function (estradiol levels of greater than 100 pg/ml) was seen in 7 of 7, 9 of 14, 2 of 23, and 1 of 5 women with a clinical history of regular menses, irregular menses, amenorrhea, and hysterectomy, respectively. Supraphysiological levels of estradiol (greater than 350 pg/ml) were noted in 13 of 19 women with endocrine evidence of ovarian function. Supraphysiological progesterone levels (greater than 20 ng/ml) were also seen in 5 of 7 of the regularly menstruating women taking tamoxifen. Supraphysiological levels of estradiol were associated with elevated follicle-stimulating hormone levels, but there was no mean change in the luteinizing hormone levels. Minimum and maximum serum follicle-stimulating hormone levels were 1.9 and 9.0 mIU/ml in the 12 normal women and 5.2 and 24.3 mIU in the 13 women with supraphysiological estradiol levels. Our findings demonstrate that the majority of women who continue to menstruate while taking continuous tamoxifen following cytotoxic chemotherapy have supraphysiologic estradiol levels. This is a potential mechanism for failure of tamoxifen therapy in these premenopausal women.

Adenocarcinoma↗
PubMed1988

In vitro estrogenic actions in rat and human cells of hydroxylated derivatives of D16726 (zindoxifene), an agent with known antimammary cancer activity in vivo.

A series of 2-phenyl-1-ethyl-3-methylindoles with or without a hydroxyl group in the para position of the phenyl ring and the 5 or 6 position of the indole nucleus were compared with 17 beta-estradiol in the stimulation of (a) prolactin production in rat pituitary cells in primary culture, (b) progesterone receptor synthesis in MCF-7 cells, and (c) proliferation of MCF-7 cells. All compounds were less active than estradiol but all derivatives including D15414, the hydroxylated metabolite of D16726 (zindoxifene, a known antitumor agent against mammary cancer) were fully estrogenic. Hydroxyl groups at the para position of the phenyl ring and 6 position of the indole nucleus conferred the highest estrogen potency [ED50 (drug concentration producing 50% of maximum activity) in all assays around 10(-10) M]. Moving or eliminating the hydroxyl on the indole ring markedly reduced the estrogen potency; however, an even more dramatic reduction in estrogenic activity was produced by removing the hydroxyl of the phenyl ring.

Animals↗
PubMed1988

Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse.

The effects of the antiestrogen tamoxifen (TAM) on the growth of two hormone-sensitive human tumors have been examined in athymic mice. The endometrial tumor, EnCa101, was stimulated to grow by TAM either alone or when combined with estradiol. This contrasted with the nonstimulation of the breast tumor, MCF-7, by TAM alone and the antagonist action of TAM on estradiol-stimulated growth of MCF-7 tumors. The individual tumor responses were observed even when the two tumor types were implanted on opposite sides of the same animal. This suggests that host metabolism of TAM does not dictate tissue response. The conclusion is supported by the finding of very similar patterns of metabolites in the two tumors after administration of [ring-3H]TAM. Tissue metabolism therefore is unlikely to be involved. Progesterone receptor levels were higher in estradiol (376 +/- 35 fmol/mg cytosol protein)- or TAM (317 +/- 37 fmol/mg cytosol protein)-stimulated EnCa101 tumors than control (42 +/- 5 fmol/mg cytosol protein) and increased further with combined treatment (485 +/- 75 fmol/mg cytosol protein). Estrogen receptor levels, however, were lower in estradiol (45 +/- 11 fmol/mg cytosol protein)-treated tumors than control (92 +/- 13 fmol/mg cytosol protein) but higher than control in TAM (200 +/- 15 fmol/mg cytosol protein)-treated tumors. Tumors grown with estradiol and TAM had lower estrogen receptor levels (130 +/- 7 fmol/mg cytosol protein) than tumors grown with TAM alone. Estrogen receptor levels indicate that TAM may not be acting exactly as estradiol in the EnCa101 tumor. Overall, these findings suggest that the disparate pharmacology of TAM is a tissue-specific phenomenon.

Animals↗
PubMed1988

The development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole.

Tamoxifen, a nonsteroidal antiestrogen, is now the endocrine treatment most widely used in breast cancer, both in the adjuvant and advanced disease settings. Here we will trace the development of tamoxifen for advanced breast cancer in postmenopausal patients, consider the biological basis for the recent successful use of tamoxifen for long-term adjuvant therapy, and discuss the use of tamoxifen in premenopausal patients with advanced disease. In part, this will be a historical review offered as a tribute to the late Dr. Arthur L. Walpole, who must receive the chief credit for the discovery of tamoxifen and its subsequent application as an anticancer agent.

Breast Neoplasms↗
PubMed1988

Bone mineral density in women with breast cancer treated with adjuvant tamoxifen for at least two years.

While in limited animal studies tamoxifen is reported to protect against loss of bone mineral, data in humans are lacking. We measured bone mineral density (BMD) using single photon absorptiometry at the radius and dual photon absorptiometry at the lumbar spine in breast cancer patients treated with chemotherapy at our institution. In this group, 37 women were not treated with tamoxifen (NT) and 48 women were treated with tamoxifen (T) for at least two years. Younger age, greater weight and height, premenopausal status, and shorter time since menopause were found to be significant predictors of greater BMD. Tamoxifen-treated women had been postmenopausal for more years (p = 0.012). Regression analyses used to adjust for differences in risk of bone loss did not reveal significant differences in BMD between the two groups of women. For the postmenopausal women (27 NT and 34 T subjects), the adjusted mean BMD (g/cm2) at the spine was 1.11 (NT), 1.11 (T) (p = 0.93); and at the radius 0.63 (NT), 0.62 (T) (p = 0.30). This limited retrospective study suggests that tamoxifen does not have 'anti-estrogenic' effects on BMD.

Adult↗
PubMed1988

Estradiol-stimulated growth of MCF-7 tumors implanted in athymic mice: a model to study the tumoristatic action of tamoxifen.

Ovariectomized athymic (nude) mice were inoculated (10(7) cells) with the breast cancer cell line, MCF-7, into the axillary mammary fat pads. Tumors did not grow unless animals were implanted with a 1.7 mg estradiol sustained (8-week)-release cholesterol pellet. Co-implantation with tamoxifen (5 mg, 4-week release) caused an inhibition of estradiol-stimulated growth but did not cause tumor growth when implanted alone. The metabolism of [3H]tamoxifen was determined in the athymic mouse bearing MCF-7 tumors. Metabolites in the liver, uterus and tumor were determined by TLC. The principal metabolite in each of the tissues was 4-hydroxytamoxifen (by comparison of Rfs with authentic standards). Studies with 4-hydroxytamoxifen and N-desmethyltamoxifen (the principal metabolites in patients) showed that each was effective in inhibiting estradiol-stimulated tumor growth. However, tumor growth could be reactivated by treatment with estradiol alone. In a separate experiment, tumor-implanted animals were treated with tamoxifen for 1, 2 and 6 months. Tamoxifen did not cause tumor growth. Nevertheless, tumor growth was reactivated by estradiol on each occasion. These studies confirm the tumoristatic actions of tamoxifen and strongly support the view that therapy must be given indefinitely to patients to control tumor recurrence. The athymic mouse model can be used in the future to determine the efficacy of novel antiestrogens and the development of antiestrogen drug resistance.

Animals↗
PubMed1988

Active immunization to luteinizing hormone releasing hormone to inhibit the induction of mammary tumors in the rat.

Immunization of female rats with a bovine serum albumin-luteinizing hormone releasing hormone conjugate results in suppression of dimethylbenzanthracene mammary tumor incidence. Tumor incidence was 1.3, and 1.29 tumors per rat in bovine serum albumin alone (n = 10) and unimmunized (n = 18) control groups, but no tumors were found in the bovine serum albumin-luteinizing hormone releasing hormone conjugate immunized animals (n = 10). In a second experiment immunization with bovine serum albumin-luteinizing hormone releasing hormone conjugates reduced tumor incidence to 0.3 tumors per rat (n = 10) from the 1.2 tumors per animal seen in the control animals (n = 10) immunized with bovine serum albumin alone. Bovine serum albumin-luteinizing hormone immunization caused the production of anti-LHRH antibodies, an interruption of estrous cycles, lowered serum estradiol and progesterone levels, and atrophy of the ovaries and uteri. Immunization BSA-hormone conjugates is a novel anti-tumor strategy.

9,10-Dimethyl-1,2-benzanthracene↗