Long-term adjuvant tamoxifen therapy for breast cancer

Jordan, V. Craig

doi:10.1007/bf01806350

Cited by 113 publications

(53 citation statements)

References 76 publications

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“…However, steady-state tissue concentrations of TAM in rats and humans, including in the hepatic tissue, are 60 -70 times higher than in serum (Lien et al, 1991), due to its strong partitioning in biomembranes (Custódio et al, 1991), and at least 4 weeks of administration are required to reach steadystate drug concentrations (Jordan, 1990). Therefore, the estimated drug concentrations in peripheral tissues may reach values (approximately 10 to 50 M) in the range of our studies.…”

Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 69%

“…In conclusion, this work demonstrates that TAM, in the range of concentrations used, which are related with those reached in tissues (Jordan, 1990;Lien et al 1991;Custódio et al, 1991), may induce substantial alterations on cellular energetic charge as a consequence of the uncoupling of oxidation from phosphorylation, rendering the mitochondria unable to fulfill the cell energy requirements due to the disruption of the mitochondrial inner membrane and by activation of mitochondrial ATPase. These different effects may explain the process of cell death induced by this anticancer agent in different cell types, including ER-negative breast cancer (Jordan 1990), lung adenocarcinoma (Croxtall et al, 1994), prostate cancer (Bergan et al, 1999), ovarian carcinoma (Trope et al, 2000), virus (Laurence et al, 1990), and bacteria (Luxo et al, 1996), since ATP is required to maintain the cell viability.…”

Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 74%

“…Tamoxifen usually is administrated at a daily dose of 20 mg/kg body wt and the range of TAM serum levels is between 50 and 300 ng/ml (approximately 0.8 M) (Jordan 1990). However, steady-state tissue concentrations of TAM in rats and humans, including in the hepatic tissue, are 60 -70 times higher than in serum (Lien et al, 1991), due to its strong partitioning in biomembranes (Custódio et al, 1991), and at least 4 weeks of administration are required to reach steadystate drug concentrations (Jordan, 1990).…”

Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 99%

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Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Cardoso

Custódio

Almeida

et al. 2001

Toxicology and Applied Pharmacology

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Tamoxifen (TAM), the widely prescribed drug in the prevention and therapy of breast cancer, is a well-known modulator of estrogen receptor (ER) that also inhibits the proliferation of different cell types that lack the ER. However, the ER-independent action mechanisms of TAM and its side effects have not been yet clarified. Mitochondria are essential in supporting the energy-dependent regulation of cell functions. Changes in mitochondria result in bioenergetic deficits leading to the loss of vital functions to cell survival. Therefore, this study describes the effects of TAM on mitochondrial bioenergetics, contributing to a better understanding of the biochemical mechanisms underlying the multiple antiproliferative and toxic effects of this drug. TAM at concentrations above 20 nmol/mg protein, preincubated with isolated rat liver mitochondria at 25°C for 3 min, significantly depresses, in a dose-dependent manner, the phosphorylation efficiency of mitochondria as inferred from the decrease in the respiratory control and ADP/O ratios, the perturbations in mitochondrial transmembrane potential (⌬⌿), the fluctuations associated with mitochondrial energization, and the phosphorylative cycle induced by ADP. Furthermore, TAM at up to 40 nmol/mg protein stimulates the rate of state 4 respiration and at higher concentrations it strongly inhibits state 3 and uncouples the mitochondrial respiration. The stimulation of state 4 respiration parallels the decrease of ⌬⌿ as a consequence of proton permeability. The TAM-stimulatory action of ATPase is also observed in intact mitochondria, suggesting that TAM promotes extensive permeability to protons due to destructive effects in the structural integrity of the mitochondrial inner membrane. These multiple effects of TAM on mitochondrial bioenergetic functions, causing changes in the respiration, phosphorylation efficiency, and membrane structure, may explain the cell death induced by this drug in different cell types, its anticancer activity in ER-negative cells, and its side effects. © 2001 Academic Press Key Words: tamoxifen; anticancer drug; mitochondria; respiration rate; mitochondrial transmembrane potential; mitochondrial proton leak; membrane disruption.Tamoxifen (TAM) is the most used nonsteroidal antiestrogen drug for chemotherapy and chemoprevention of breast cancer (Neven and Vernaeve, 2000;Radmacher and Simon, 2000). The antiproliferative effects of TAM in estrogen-dependent breast cancer cells are mediated by high-affinity binding to the estrogen receptor (ER) (Coezy et al., 1982). However, TAM inhibits also the growth of ER-negative breast cancer cells and other cell types that lack ER (Couldwell et al., 1993;Croxtall et al., 1994;Charlier et al., 1995). Actually, TAM has been reported to have several physiological effects that are ER independent, including sensitization of resistant tumor cells to many chemotherapeutic agents (Altan et al., 1999) and several pleiotropic effects both in vivo and in vitro and references therein). Moreover, it has been reported that...

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Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 69%

Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 74%

Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 99%

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Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Cardoso

Custódio

Almeida

et al. 2001

Toxicology and Applied Pharmacology

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“…The presence of functional oestrogen receptors (ER) in breast cancer predicts the clinical response of a patient to endocrine therapy (Jordan, 1994). ER-positive patients respond well to antioestrogens such as tamoxifen, which produces a favourable response in up to 60% of the patients (Lemer and Jordan, 1996).…”

mentioning

confidence: 99%

“…ER-positive patients respond well to antioestrogens such as tamoxifen, which produces a favourable response in up to 60% of the patients (Lemer and Jordan, 1996). Unfortunately, hormone dependency is ultimately lost in advanced breast cancer after an initial response to the therapy.…”

mentioning

confidence: 99%

Methylation of CpG island is not a ubiquitous mechanism for the loss of oestrogen receptor in breast cancer cells

Chen

Ko²,

Yang³

et al. 1998

Br J Cancer

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Summary Methylation has been shown to play an important role in the down-regulation of oestrogen receptors (ER) in breast cancer cells. One critical question that remains unclear is whether methylation can account for the loss of ER expression in cells derived from an ERpositive cell line. This laboratory has established an in vitro cell system using long-term growth of human ER-positive breast cancer cell line T47D in oestrogen-free medium. A clonal cell line, T47D:C4:2 (C4:2), has been characterized. Unlike T47D:A18 (A18), which is a T47D line maintained in oestrogen medium, C4:2 has lost the expression of ER and hormone responsiveness. DNA fingerprinting and restriction fragment length polymorphism (RFLP) analysis results confirmed that C4:2 was of the same lineage as A18. These cell lines provide an invaluable system to study the mechanism of ER expression and regulatory pathways leading to hormone-independent growth. The results here clearly demonstrate that the ER CpG island in C4:2 cells remains unmethylated. The loss of ER in the cell line must be due to mechanisms other than methylation. We also evaluated the ER CpG island in the MDA-MB-231 :10A (10A) cell line, which is a clone from the MDA-MB-231 line obtained from ATCC and the DNA from the MDA-MB-231 cell line used in the original report. Unlike the cell line from the report, which showed a full methylation pattern in the island, the 1 OA line only showed a partial methylation pattern in the CpG island. Possible mechanisms pertaining to the heterogeneous methylation pattern of the ER CpG island in the breast cancer cells are discussed.

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The relationship of chemotherapeutic and endocrine intervention on natural killer cell activity in human breast cancer

Brenner¹,

Margolese

1991

Cancer

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Peripheral blood natural killer (NK) activity against K562 target tumor cells was monitored in patients with breast cancer receiving no treatment, combination chemotherapy, and/or endocrine therapy, NK activity in untreated Stage I patients with no evidence of disease (ned) was significantly higher than in healthy controls. NK activity was shown to decline in individuals with cytotoxic drug therapy (P equals 0.036). There also were reductions in lymphocyte recoveries concomitant with chemotherapeutic intervention (P less than 0.001). Lymphocyte counts were incorporated in a calculation of absolute NK activity that more accurately reflected the significant reduction in NK activity that occurred in patients with localized and systemic disease on chemotherapy. Different chemotherapeutic agents were found to selectively affect NK activity. Stage I1 patients on phenylalanine mustard (P)/ 5-fluorouracil (F) (PF) and cyclophosphamide (C)/methotrexate (M)/S-fluorouracil (F) (CMF) protocols showed significant reductions in overall NK activity relative to healthy controls and Stage I patients with ned. Patients on P/doxorubicin (A)/F/ tamoxifen (Tx) (PAFT) protocols showed reduced NK activity relative to Stage I patients. Patients on the short-dose C/A (CA) protocol showed normal levels of overall NK activity. High-risk Stage I patients on methotrexate (M)/F (MF)with sequential leucovorin rescue and patients with metastatic disease on endocrine therapy, ie., Tx or megestrol acetate (Meg) showed overall NK activities in the range of healthy controls. Patients with systemic disease on CMF, CMF/ vincristine/prednisone (CMFVP), vinblastine/A/thiotepa/fluoxymesterone (VATH), mitomycin/mitoxantrone (MtMx), and A regimens showed overall levels of absolute NK that were significantly less than either healthy controls or metastatic patients undergoing endocrine therapy. NK cytolytic data, monitored at multiple effector to target ratios, were subjected to exponential regression analysis. The elevation of NK cell responses in Stage I patients with ned and the decline of NK cell responses with cytotoxic chemotherapy were due to alterations in the maximal plateau levels of NK cell cytotoxicity represented by the A (asymptote) values. The k values obtained on regression analysis and indices of the relative killing capacities of individual NK cells remained unaltered in all populations. These results suggest that the cytolytic lymphocyte NK pool, elevated in Stage I patients with cancer, selectively declines as a result of cytotoxic therapy. Cancer 68:482-488,1991.

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Long-term adjuvant tamoxifen therapy for breast cancer

Cited by 113 publications

References 76 publications

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Methylation of CpG island is not a ubiquitous mechanism for the loss of oestrogen receptor in breast cancer cells

The relationship of chemotherapeutic and endocrine intervention on natural killer cell activity in human breast cancer

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