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V C Jordan

Publications and source records attributed to V C Jordan.

At least 163 records · Page 9Linked to original sources
PubMed1993

Investigation of the mechanism of tamoxifen-stimulated breast tumor growth with nonisomerizable analogues of tamoxifen and metabolites.

BACKGROUND: The nonsteroidal anti-estrogen tamoxifen (TAM) is the front-line endocrine treatment for breast cancer, but disease recurrence is common. Treatment failure may occur because tumors become insensitive to TAM. Alternatively, resistance may occur because tumors become stimulated rather than inhibited by TAM. TAM-stimulated growth of MCF-7 human breast tumors has been observed in athymic mice after prolonged treatment with TAM. PURPOSE: Our purpose was to examine the mechanism of treatment failure by determining whether TAM-stimulated tumors acquire the ability to excrete TAM and its anti-estrogenic metabolites or to convert them to estrogenic compounds with weakened antiestrogenic activity. METHODS: We used high-pressure liquid chromatography to quantitate TAM and its metabolites in serum and tumors from ovariectomized athymic mice and in MCF-7 cells grown in vitro. We treated tumor-bearing mice with subcutaneous sustained-release preparations of estradiol, TAM, or a nonisomerizable (fixed-ring) analogue and then assessed the activity of these compounds on TAM-inhibited parental MCF-7 tumors and on TAM-stimulated MCF-7 TAM tumors. RESULTS: We found negligible differences in intratumoral TAM levels between TAM-inhibited parental MCF-7 tumors and TAM-stimulated MCF-7 TAM variants. We did not detect metabolite E (Met E), an estrogenic TAM metabolite, in serum or tumors. Using MCF-7 cells in vitro, we determined that the (Z) isomer of Met E, the form directly produced by TAM metabolism, must be present in the cell at a concentration of over 1000 ng/g to overcome growth inhibition by physiological levels of TAM and antiestrogenic metabolites, but the (E) isomer of Met E was effective at 10 ng/g. We reasoned that conversion of Met E from the (Z) (a weak estrogen) to (E) isomer (a potent estrogen) would be required if formation of Met E were responsible for TAM-stimulated growth. However, fixed-ring TAM, which can only form (Z) Met E, was shown to be as capable as TAM of initiating and maintaining anti-estrogen-stimulated growth of MCF-7 tumors in athymic mice. CONCLUSION: Metabolism and isomerization of TAM to estrogenic compounds is not the mechanism of TAM-stimulated growth in our model. IMPLICATION: Other potential mechanisms for TAM-stimulated growth, such as estrogen receptor mutation, must be investigated so that effective strategies can be devised to control breast cancer once therapy fails.

Animals↗
PubMed1993

Targeted hormone therapy for breast cancer.

Large-scale studies now provide relatively clear guidelines for the clinician on antiestrogen treatment in various patient populations and subgroups. Future challenges are to determine whether antiestrogens might be used for prevention, to identify the environmental and genetic causes of breast cancer, and to develop new approaches to this tumor, such as antiprogestins.

Age Factors↗
PubMed1993

The estrogenic activity of synthetic progestins used in oral contraceptives.

BACKGROUND: Oral contraceptives (OC) contain an orally active estrogen in combination with an orally active synthetic progestin derived from 19-nortestosterone. OC have had an enormous positive impact on public health for the past three decades, and in the main, there has been a remarkably low incidence of troublesome side effects. Although estrogens are implicated in an increased incidence of breast and endometrial cancer, epidemiologic studies have not provided convincing evidence to support a direct correlation between OC use and an increase in breast cancer incidence. By contrast, OC do cause a decrease in the incidence of endometrial and ovarian carcinoma. During the past decade, several isolated reports have linked an increased incidence of breast cancer with the use of synthetic progestins. No mechanism for the proliferative potential of progestins has been offered. Therefore, the authors investigated this problem to formulate a hypothesis, based on laboratory data, that might be evaluated in populations at risk. METHODS: The synthetic progestins (19-nortestosterone derivatives) chosen for the study were norethynodrel, norethindrone, norgestrel (levonorgestrel), and gestodene. These were compared with the actions of medroxyprogesterone acetate (MPA). To determine whether the progestins produced their effects via the ER, the cells were transfected with a chloramphenicol acetyl transferase (CAT) reporter gene containing an estrogen response element only activated by ER. RESULTS: The 19-nortestosterone derivatives all stimulated the growth of estrogen receptor (ER)-positive but not ER-negative breast cancer cells in culture. Antiestrogens, but not the antiprogestin mifepristone (also known as RU 486), inhibited progestin-stimulated cell proliferation. MPA did not stimulate cell proliferation. All the synthetic progestins that increased replication also activated CAT. Activation was blocked by antiestrogens but not by mifepristone; the synthetic progestin MPA was inactive. CONCLUSIONS: These studies provided direct evidence that some synthetic progestins exert estrogenic effects through the ER. The results demonstrated that progestins can have a dual effect on estrogen target tissues either to stimulate or differentiate cells. The results suggest that some beneficial estrogen-like effects could be produced by synthetic progestins (e.g., bone preservation), but epidemiologic studies of OC use should focus of the "total estrogen" content to establish whether some formulations place some groups of women at greater risk of having breast cancer.

Breast Neoplasms↗
PubMed1993

Molecular mechanisms of resistance to tamoxifen therapy in breast cancer.

Clinical data suggest that the use of adjuvant tamoxifen citrate (Nolvadex) for a minimum of 5 years, and possibly indefinitely, will result in maximal antitumor benefit. There is concern that long-term tamoxifen maintenance therapy may result in the induction of drug resistance. This article reviews the potential molecular mechanisms of resistance to tamoxifen and explores the possibility of tamoxifen-stimulated tumor growth.

Binding, Competitive↗
PubMed1993

Human recombinant interferon-beta SER and tamoxifen: growth suppressive effects for the human breast carcinoma MCF-7 grown in the athymic mouse.

Tamoxifen is the endocrine treatment of choice for breast cancer. However, resistance to therapy and patient relapse inevitably occurs. In future treatment schedules, interferons could be administered with tamoxifen, in an attempt to prevent disease recurrence. Human recombinant interferon-beta SER (rIFN-beta SER) inhibited the growth in vitro of the estrogen receptor (ER) positive breast cancer cell line MCF-7 and the ER negative breast cancer cell line MDA-MB-231. This inhibitory effect was achieved at doses of 50 U/ml and above. The growth of MCF-7 tumors in estradiol-stimulated athymic mice was greatly inhibited by high dose rIFN-beta SER treatment (10(6)U/day). In spite of the impressive antitumor effects upon MCF-7 tumors, rIFN-beta SER had no effect upon ER levels within the tumors at either the RNA or protein level, as measured by Northern blotting and ER-EIA respectively. High dose rIFN-beta SER (10(6)U/day) did result in some inhibition in the growth in vivo of the tamoxifen-stimulated MCF-7 variant MCF-7 TAM, although not to the same extent as was observed with the estradiol-stimulated MCF-7 tumors. rIFN-beta SER was also administered to animals bearing MCF-7 tumors and treated with estradiol and tamoxifen. In the animals undergoing high dose therapy (10(6)U/day), tumor growth was completely suppressed. Furthermore, tumor growth continued to be suppressed in those animals in which the rIFN-beta SER therapy was halted and the tamoxifen capsule removed. No tumors were observed in spite of the environment of estradiol stimulation. Thus, the combination of interferon and tamoxifen was totally growth suppressive for MCF-7 xenografts in nude mice.

Animals↗
PubMed1993

The effects of intermittent progesterone upon tamoxifen inhibition of tumor growth in the 7,12-dimethylbenzanthracene rat mammary tumor model.

The development of endometrial cancer is a potential risk during long-term tamoxifen therapy for breast cancer. In order to protect the uterus, progestin treatment has been proposed for these patients. However, within the 7,12-dimethylbenzanthracene-induced rat mammary model, progesterone is known to reverse the antitumor effects of tamoxifen. This study shows that progesterone administered intermittently still reverses the antitumor effects of tamoxifen in this model. This effect of progesterone is not due to a decrease in the tissue levels of tamoxifen, and may be direct, via the progesterone receptor.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

William L. McGuire Memorial Symposium. Drug resistance to tamoxifen during breast cancer therapy.

Breast cancer is the most common malignancy occurring in Western women, and is one of the leading causes of cancer mortality. The nonsteroidal antiestrogen tamoxifen has been shown to be an effective treatment for pre and postmenopausal women with all stages of the disease. Tamoxifen provides effective palliation when used to treat patients with advanced disease, and adjuvant tamoxifen therapy produces significant increases in both disease-free and overall survival (Early Breast Cancer Trialists Collaborative Group. Lancet 339:1-15, 71-85, 1992). Data from the laboratory have shown that the primary action of tamoxifen is tumoristatic rather than tumoricidal, and long-term therapy is therefore recommended. Unfortunately, many patients experience disease progression while taking tamoxifen. Some tamoxifen resistant tumors may remain sensitive to alternative endocrine therapies, while others may become refractory to any hormonal manipulation. Many models have been developed in vitro and in vivo to study the progression of breast cancer growth from tamoxifen sensitive to tamoxifen resistant. We and others have used long-term estrogen deprivation and long-term tamoxifen exposure to develop cell lines and tumors capable of growth in the presence of clinically relevant tamoxifen concentrations. Recently our laboratory has also shown that mutations in the estrogen receptor can cause an antiestrogen-occupied receptor to behave as though it were occupied by an estrogen. Breast cancer is a highly heterogeneous disease and it is likely that the mechanisms which cause tamoxifen resistant growth are equally heterogeneous. Several of the models from our laboratory and others which may contribute to an understanding of this complex phenomenon are discussed here.

Breast Neoplasms↗
PubMed1993

A model to describe how a point mutation of the estrogen receptor alters the structure-function relationship of antiestrogens.

The antiestrogen tamoxifen [(Z)-1(p-beta-dimethylamino-ethoxyphenyl)-1,2- diphenylbut-1-ene] is an effective anticancer agent for the treatment of hormone responsive breast cancer. Previous studies have demonstrated that a point mutation in the estrogen receptor (ER) resulted in an alteration of the pharmacology of 4-hydroxytamoxifen, the active metabolite of tamoxifen (Jiang et al, Mol Endocrinol 6:2167-2174, 1992). We have extended our studies to evaluate the effect of a point mutation, a Val substitution for Gly at amino acid 400 in the ligand binding domain of ER, on the pharmacology of other antiestrogens in ER stable transfectants derived from the ER-negative breast cancer cell line MDA-MB-231 CL10A. The compounds were tested with or without estradiol-17 beta (E2) for their effects on cell growth in cells expressing the wild type ER (S30) or the mutant ER (ML alpha 2H) or in control antisense ER transfectant AS23 which does not express ER protein. MCF-7 cells, which express the wild type ER, were also used as a control. The growth of AS23 cells was not affected by any of the compounds at a concentration of 1 microM. E2 stimulated the growth of MCF-7 cells but inhibited the growth of ER transfectants S30 and ML alpha 2H. The ML alpha 2H cells were about 10 to 100-fold less sensitive to E2 and antiestrogens than S30 and MCF-7 cells. Keoxifene, an antiestrogen with a high affinity for the ER, maintained antiestrogenic activities in both ER transfectants and MCF-7 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1993

Subcellular compartmentalization of MCF-7 estrogen receptor synthesis and degradation.

Turnover of the estrogen receptor protein was studied by using enucleation of human breast cancer-derived MCF-7 cells, to examine receptor synthesis and receptor degradation in the separated cytoplasmic compartment (cytoplasts) and nuclear compartment (nucleoplasts). Cytoplasts synthesized estrogen receptors as measured by both hormone-binding and immunoassay, while estrogen receptors (but not progesterone or glucocorticoid receptors) were rapidly degraded in nucleoplasts with a half-life of 3-4 h. Little or no degradation of estrogen receptors in cytoplasts was observed under several conditions. Interestingly, MCF-7 cytoplasts contained approximately 15% of the cell's estrogen receptors, which were not 'translocated' by treatment with 17 beta-estradiol before enucleation. We conclude that the estrogen receptor can be synthesized at least to a hormone binding form in the cytoplasm alone without requiring processing in the nucleus, while the nucleus (or perinuclear cytoplasm) is the primary site of degradation of the estrogen receptor protein. In addition, the presence of a population of estrogen receptors that is cytoplasmic but nontranslocatable may need to be considered in the subcellular localization and actions of steroid receptors.

Brain Neoplasms↗
PubMed1993

Regulation of the levels of three transforming growth factor beta mRNAs by estrogen and their effects on the proliferation of human breast cancer cells.

Transforming growth factor (TGF) beta is a potent regulator of cell proliferation and may play a role in breast cancer cell growth. We have evaluated the regulation of TGF beta 1, TGF beta 2, and TGF beta 3 mRNAs by 17 beta-estradiol (E2) and 4-hydroxytamoxifen (MOH) in estrogen receptor-positive (ER(+)) MCF-7 and estrogen receptor-negative (ER(-)) MDA-MB-231 human breast cancer cells. We also determined the effect of TGF beta 1, TGF beta 2, and TGF beta 3 on the proliferation of these cells. Cells were deprived of estrogen before the addition of hormones, and mRNA was measured by Northern blot analysis. We found that MCF-7 cells expressed mRNAs of all three TGF beta species. Treatment of MCF-7 cells with 10(-10) M E2 for 7 days resulted in a dramatic decrease in the TGF beta 2 and TGF beta 3 mRNA levels, but not in the TGF beta 1 mRNA level. MOH was found to block these effects. In addition, the regulation of TGF beta 2 and beta 3 gene expression occurs at both transcriptional and post-transcriptional levels. There is an inverse correlation between E2-induced growth and levels of TGF beta 2 and TGF beta 3 mRNA. In contrast to MCF-7 cells, MDA-MB-231 cells expressed TGF beta 1 and TGF beta 2 mRNAs but TGF beta 3 mRNA was not detected, and the TGF beta 1 and TGF beta 2 mRNAs were not regulated by estrogens or antiestrogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1993

Suppression of serum insulin-like growth factor-1 levels in breast cancer patients during adjuvant tamoxifen therapy.

Serial IGF-1 levels in patients prior to and during adjuvant tamoxifen (TAM) treatment were followed in a retrospective study. Serum IGF-1 levels were determined by radioimmunoassay in 19 patients taking TAM and 19 controls, matched for age, body weight and other treatments. IGF-1 levels at 2 years were significantly lower in TAM patients (P < or = 0.05) compared to control patients. We observed a significant mean drop from pretreatment to treatment IGF-1 levels by 19.9% in the TAM group (P < or = 0.005), but also noted a mean 11.4% decline in the control group (P < or = 0.025). A subgroup analysis suggested that premenopausal were relatively resistant to the IGF-1 lowering effects of TAM as compared to postmenopausal women.

Adult↗
PubMed1993

Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism.

There is great concern over the long-term influence of oral contraceptives on the development of breast cancer in women. Oestrogens are known to stimulate the growth of human breast cancer cells, and this laboratory has previously reported (Jeng & Jordan, 1991) that the 19-norprogestin norethindrone could stimulate the proliferation of MCF-7 human breast cancer cells. We studied the influence of the 19-norprogestins norgestrel and gestodene compared to a 'non' 19-norprogestin medroxyprogesterone acetate (MPA) on MCF-7 cell proliferation. The 19-norprogestins stimulated proliferation at a concentration of 10(-8) M, while MPA could not stimulate proliferation at concentrations as great as 3 x 10(-6) M. The stimulatory activity of the 19-norprogestins could be blocked by the antioestrogen ICI 164,384, but not by the antiprogestin RU486. Transfection studies with the reporter plasmids containing an oestrogen response element or progesterone response element (vitERE-CAT, pS2ERE-CAT, and PRE15-CAT) were performed to determine the intracellular action of norgestrel and gestodene. The 19-norprogestins stimulated the vitERE-CAT activity maximally at 10(-6) M, and this stimulation was inhibited by the addition of ICI 164,384. MPA did not stimulate vitERE-CAT activity. A single base pair alteration in the palindromic sequence of vitERE (resulting in the pS2ERE) led to a dramatic decrease in CAT expression by the 19-norprogestins, suggesting that the progestin activity required specific response element base sequencing. PRE15-CAT activity was stimulated by norgestrel, gestodene and MPA at concentrations well below growth stimulatory activity. This stimulation could be blocked by RU486. These studies suggest that the 19-norprogestins norgestrel and gestodene stimulate MCF-7 breast cancer cell growth by activating the oestrogen receptor.

Base Sequence↗
PubMed1993

Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer.

Tamoxifen has been found to be a safe and effective treatment for all stages of breast cancer. Long term tamoxifen therapy is associated with some rare, but potentially serious, side effects so patients should be carefully monitored. However, long term tamoxifen therapy is also associated with a number of physiological benefits over and above its tumouristatic action. These benefits include a decrease in the development of contralateral breast cancer, the maintenance of bone density in postmenopausal women and a decrease in cardiovascular disease. The successful application of tamoxifen to treat breast cancer has increased enthusiasm to test its worth to prevent breast cancer. Although there are individual requests by patients for tamoxifen to prevent breast cancer, individual treatment is inappropriate. Tamoxifen can only be adequately evaluated as a preventive in randomized, double-blind clinical trials. These trials are in place and physicians should encourage women to participate and establish a new therapeutic option as rapidly as possible.

Breast Neoplasms↗
PubMed1993

Estrogenic actions of RU486 in hormone-responsive MCF-7 human breast cancer cells.

Previously, we demonstrated that the progestin components (19-nortestosterone derivatives) in oral contraceptives are able to stimulate human breast cancer cell proliferation via an estrogen receptor (ER)-mediated mechanism. We now examine RU486, an antiprogestin, to determine whether it has estrogenic properties because it is also a 19-nortestosterone derivative. We found that RU486 stimulated the growth of MCF-7 human breast cancer cells at a concentration of 10(-6) M, which is similar to the pharmacological concentration (micromolar range) found in women taking RU486. The antiestrogens 4-hydroxytamoxifen and ICI 164,384 blocked RU486-induced cell proliferation. The estrogenic activity of RU486 is not due to impurities or aromatization to estrogenic metabolites. To determine whether the proliferative action of RU486 was mediated through the ER, cells were transfected with a chloramphenicol acetyltransferase reporter gene under the control of an estrogen response element derived from the Xenopus laevis vitellogenin 2A gene. We found that RU486 was able to induce chloramphenicol acetyltransferase activity at the concentrations that stimulated cell proliferation, and this induction was blocked by the addition of 4-hydroxytamoxifen and ICI 164,384. The estrogenic potential of RU486 to regulate ER target gene expression was also investigated. We found that, like 17 beta-estradiol (E2), RU486 was able to alter the expression and synthesis of progesterone receptor. The level of progesterone receptor (145 and 186 fmol/mg cytosol protein, respectively) was increased significantly compared to the control value (3 fmol/mg cytosol protein) with the addition of 10(-6) M RU486 or 10(-10) M E2, as determined by an enzyme immunoassay. The levels of transforming growth factor-beta 2 (TGF beta 2) and TGF beta 3 mRNA, but not TGF beta 1 mRNA, were decreased dramatically with the addition of 10(-6) M RU486. This is consistent with the effects of E2 on TGF beta expression. Therefore, RU486 has estrogen-like activities in its regulation of ER target gene expression. These results demonstrate that RU486 is a weak estrogen in human breast cancer cells and suggest that the RU486-induced cell proliferation is mediated via ER. The novel finding that RU486 exhibits some estrogen-like activity may be important for the interpretation of its action at high dosages as an abortifacient and also if RU486 is going to be evaluated clinically, again at high doses, for the treatment of breast cancer.

Breast Neoplasms↗
PubMed1993

A risk-benefit assessment of tamoxifen therapy.

Tamoxifen is the endocrine treatment of choice for all women with hormonally responsive breast cancer. 30 years of experience in both the laboratory and clinical setting have shown tamoxifen to be an effective adjuvant treatment with minor short term adverse effects. However, as therapeutic use has extended to 5 years and beyond, and as clinical trials begin which will assess the effectiveness of tamoxifen as a preventive treatment, concern about possible long term adverse effects is justified. Tamoxifen has an estrogen-like influence on the skeletal and cardiovascular systems, resulting in decreases in both postmenopausal bone loss and low density lipoprotein (LDL) levels. These effects will, it is hoped, result in decreases in the incidences of osteoporosis and coronary heart disease, which are major causes of morbidity and mortality in the postmenopausal age group. Tamoxifen therapy also results in decreased rates of contralateral breast cancer. Long term tamoxifen treatment may result in a small increase in the incidence of endometrial and/or hepatocellular carcinoma, but with millions of women taking tamoxifen for long periods, such small increases in incidence translate to a significant number of women at risk. Tamoxifen is clearly beneficial for short term treatment, but the clinical decision of tamoxifen use in the long term must be made on the individual benefits versus risks of tamoxifen treatment.

Animals↗
PubMed1993

Risk factors and the prevention of breast cancer with tamoxifen.

Oestrogen is intimately involved in the growth and development of breast cancer. Tamoxifen, a non-steroidal anti-oestrogen, not only is an effective adjuvant therapy for node positive and node negative disease, but also has several attractive pharmacological features that have enhanced interest in testing it as a preventive drug for breast cancer in high risk women. Tamoxifen is known to prevent contralateral breast cancer, but it also has significant oestrogenicity for reducing circulating cholesterol and preventing bone loss in the lumbar spine of postmenopausal women. Several clinical trials have been initiated around the world; however, there has been increasing concern about the safety of tamoxifen. Nevertheless, current reports indicate that there is little risk of developing endometrial and liver cancer, although further clinical studies must be planned. Concerns about retinal and thromboembolic problems remain anecdotal, and again additional research is essential. The prevention trials with tamoxifen are necessary to establish the worth and feasibility of a pharmacological intervention. If tamoxifen is found to be of value to prevent breast cancer in a broad population, then the future ability to predict breast cancer through molecular markers will provide the physician for the first time with a therapeutic option to treat the targeted patient.

Breast Neoplasms↗
PubMed1992

High-dose oral tamoxifen, a potential multidrug-resistance-reversal agent: phase I trial in combination with vinblastine.

BACKGROUND: P-glycoprotein mediates resistance to natural-product anti-neoplastic agents like vinblastine through an active transport process resulting in reduced intracellular concentration of these agents. The triphenylethylene antiestrogen tamoxifen and its major metabolite N-desmethyltamoxifen at concentrations of 4-6 microM enhance the intracellular concentration of natural-product antineoplastics and augment the cytotoxicity of such drugs three-fold to 10-fold in a variety of human and murine cell lines. PURPOSE: On the basis of these preclinical findings, we conducted a phase I clinical trial of high-dose, oral tamoxifen administered in conjunction with a 5-day continuous infusion of vinblastine. METHODS: We studied 53 patients with advanced epithelial tumors. Tamoxifen was given orally as a loading dose on day 1, followed by two doses a day on days 2-13. Vinblastine was given as a 120-hour continuous infusion (1.5 mg/m2 per day) on days 9-13 of each tamoxifen course. The starting dose of tamoxifen was 40 mg/m2 administered twice a day following a loading dose of 150 mg/m2. The maximum dose was 260 mg/m2 twice a day following a loading dose of 680 mg/m2. Treatment cycles were repeated every 28 days. RESULTS: The dose-limiting toxic effects of tamoxifen were neurologic and began within 3-5 days after the start of treatment. They consisted of tremor, hyperreflexia, dysmetria, unsteady gait, and dizziness. One patient experienced a grand mal seizure 24 hours after the last tamoxifen dose. Toxic effects were rapidly reversible. Asymptomatic prolongation of the QT interval on electrocardiogram occurred at doses of tamoxifen of 80 mg/m2 or higher given twice a day. No coagulation or ophthalmologic abnormalities occurred. Tamoxifen did not enhance the toxicity of vinblastine. Mean plasma concentrations of tamoxifen or N-desmethyltamoxifen at 260 mg/m2 tamoxifen given twice a day for 13 days were 6.04 and 6.56 microM, respectively. There was no relationship between plasma antiestrogen content and the development of neurotoxic effects. CONCLUSIONS: Tamoxifen at 150 mg/m2 given twice a day following a loading dose of 400 mg/m2 results in plasma levels of tamoxifen and N-desmethyltamoxifen of 4 and 6 microM, respectively, without dose-limiting toxicity. We recommend this dose for phase II trials of tamoxifen to modulate P-glycoprotein-mediated drug resistance. IMPLICATIONS: Our study demonstrates that high-dose tamoxifen can be safely administered and that plasma concentrations that may inhibit P-glycoprotein function can be achieved.

ATP Binding Cassette Transporter, Subfamily B, Mem↗