A laboratory model to explain the survival advantage observed in patients taking adjuvant tamoxifen therapy.
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Breast Neoplasms↗
Biomedical subjects
D M Wolf
Publications and source records attributed to D M Wolf.
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↗
Bond strength of composite to etched and sandblasted porcelain.
In vitro tensile bond strengths of composite to porcelain treated by acid etching or sandblasting were measured. A 9.5% HF gel was applied for 30, 60, 150, or 300 seconds at 23 degrees C. Al2O3 particles were applied as wet-10.2, dry-33.5, dry-48.0, or dry-78.0 microns. Average roughness (Ra) was measured by profilometry before and after each treatment. Both longer etching time and sandblasting using Al2O3 with larger particle sizes produced increased surface roughness of porcelain. Etching with 9.5% hydrofluoric acid gel produced higher bond strengths than sandblasting with a series of Al2O3 particles. Etching longer than 60 seconds produced increased cohesive failures in porcelain, whereas most failures observed with sandblasted surfaces were adhesive.
Aluminum Oxide↗
Gynecologic complications associated with long-term adjuvant tamoxifen therapy for breast cancer.
The antiestrogen tamoxifen was originally introduced as a therapy for advanced breast cancer. Today, tamoxifen is used to treat selected patients with all stages of breast cancer, and trials are underway to evaluate its effectiveness as a potential breast cancer preventive. When tamoxifen is used as an adjuvant or preventive, extended patient survival times can be expected, and concerns about iatrogenic complications arising from long-term treatment become important. This review discusses currently available laboratory and clinical data regarding the toxicology of tamoxifen and focuses in particular on the gynecologic complications potentially associated with long-term tamoxifen administration.
Breast Neoplasms↗
Bond strength of composite to porcelain treated with new porcelain repair agents.
In vitro tensile bond strengths of composite to porcelain were evaluated using three pretreatments (HF etching, sandblasting, diamond abrasion) of the porcelain, four bonding agents (Clearfil Porcelain Bond, Porcelain Liner M, Porcelain Liner M with Super-Bond C&B, and Scotchprime) and two storage conditions (24 h and thermocycling). The overall coefficient of variation was 27%. Significant differences among bond strengths were observed, with storage condition being the most important factor, followed by bonding agent and then pretreatment. Thermocycling decreased the bond strength of all samples, but samples treated with Scotchprime were affected least. For 24 h storage, Clearfil Porcelain Bond and Scotchprime had bond strengths above 23 MN/m2 to sandblasted porcelain.
Analysis of Variance↗
An estrogen receptor positive MCF-7 clone that is resistant to antiestrogens and estradiol.
The antiestrogen tamoxifen has been successfully used to control estrogen receptor (ER) and progesterone receptor positive breast cancer. However, the development of antiestrogen resistance is frequently observed in patients following long term treatment. We have studied the development of antiestrogen resistance in vitro and established an antiestrogen resistant variant of MCF-7 cells (clone 5C) after long term culture in estrogen free medium. The growth of clone 5C cells was not altered by either estradiol-17 beta or the antiestrogens 4-hydroxytamoxifen and ICI 164,384. Estrogen-stimulated progesterone receptor and reporter gene expression were markedly reduced in 5C cells compared to wild type MCF-7 cells. Only minor alteration in the levels of ER and no alteration in the affinity of ER for ligand were found in 5C cells. No mutation of ER cDNA in 5C cells was detected by polymerase chain reaction and DNA sequencing. This study demonstrates that change(s) in ER-mediated gene expression rather than the amino acid sequence of the ER itself may be associated with the development of at least one form of antiestrogen resistance.
Breast Neoplasms↗
Reversible control of oestradiol-stimulated growth of MCF-7 tumours by tamoxifen in the athymic mouse.
We investigated the ability of high concentrations of oestradiol to reverse the growth inhibitory action of tamoxifen on MCF-7 breast cancer cells in vivo. Tamoxifen inhibits the oestradiol stimulated growth of MCF-7 cells in athymic mice. Using a sustained release preparation of tamoxifen we consistently achieved serum concentrations of the drug in the 40 to 50 ng ml-1 range and much higher levels in tissues. These serum levels are sufficient to inhibit the oestrogen stimulated growth of MCF-7 tumours exposed to physiologic (i.e. 300-600 pg ml-1 serum oestradiol concentrations). However, by administering dosages that increase serum oestradiol concentrations to 900-2000 pg ml-1, mimicking the increase often observed clinically in premenopausal women taking tamoxifen, we show that the growth inhibitory action of tamoxifen can be partially reversed. Serum tamoxifen levels were elevated to nearly 400 ng ml-1 by injecting 1 mg day-1 tamoxifen (IP 3 x weekly); this dosage was more effective at inhibiting oestradiol stimulated tumour growth than subcutaneous tamoxifen capsules alone. Our data suggest that at low serum levels tamoxifen may not act optimally. There may be a need to monitor tamoxifen levels in premenopausal patients to ensure that they are high enough not to be overcome by a tamoxifen induced increase in ovarian steroidogenesis.
Animals↗
The current state of hysterosalpingography.
The authors present an overview of the current status of hysterosalpingography, discussing the advantages and disadvantages of various cannulas, contrast media, and methods of contrast medium introduction. Thirty-two figures illustrate a variety of abnormal findings including among others: intravasation of contrast medium, salpingitis isthmica nodosa, manifestations of pelvic inflammatory disease, the effects of DES exposure, Ascherman's syndrome, adenomyosis, carcinoma, polyps, myomata and developmental uterine abnormalities.
Fallopian Tube Diseases↗