Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-hydroxyandrostenedione, a potent inhibitor of the aromatase (oestrogen synthetase) system, was given to 11 patients with metastatic breast cancer. After a single 500 mg intramuscular injection a sustained reduction of serum oestradiol was observed for at least 1 week in all patients in whom the steroid was measured. 4 patients responded to treatment for periods of up to 4 months, and healing of bone metastases and reduction in size of soft-tissue metastases was evident. The only side-effects were pain at the injection site and hot flushes. 4-hydroxyandrostenedione is a new and specific aromatase inhibitor which shows promise in the treatment of patients with metastatic breast cancer.
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PMID:4-Hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer. 615 Feb 77

Aminoglutethimide (AG) has antitumor activity in disseminated breast cancer similar to that of surgical adrenalectomy. AG works by blocking conversion of aromatase enzymes necessary for conversion of androgens to estrogens. Tumor response in patients with disseminated disease has been approximately 30%, with a further 13% of patients achieving stabilization of disease. Age and previous systemic treatment did not influence response to AG, except that those who had not responded to previous endocrine responded less well to AG. Relief of bone pain occurred not only in patients whose bone metastases objectively responded but also in some patients whose disease progressed. Side effects, although significant initially, usually subsided within 3 weeks; the incidence of side effects may be related to the rate of acetylation of the drug by the liver. In randomized clinical trials, AG has been shown to be as effective as adrenalectomy and tamoxifen therapy. AG was not as well tolerated as tamoxifen, but it was more effective in patients with bone metastases.
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PMID:The role of aromatase inhibitors in breast cancer. 636 51

Treatment for advanced breast cancer is not yet curative but aims to palliate the disease to make life as symptom free and as active for as long as possible with the minimum of adverse effects of treatment. The high prevalence and often long time course of the disease leads breast cancer to make major demands on health care resources. Radiotherapy is valuable for localized lesions, but more widespread disease relies on systemic treatment. Tamoxifen is the main agent for endocrine therapy, although aromatase inhibitors and progestogens are also important. Improvements in cytotoxic chemotherapy have come as much from methods to reduce toxicity as from new agents. Intensive chemotherapy with bone marrow support has not found a routine place in advanced breast cancer, but experience gained may have more application in the adjuvant treatment of high risk operable disease. Incorporation of quality of life measures is being increasingly recognized as essential for the proper evaluation of response to treatment. Although postoperative adjuvant systemic therapy now has an established place for early breast cancer, subsequent relapse responds less well to either endocrine or cytotoxic agents. Bone metastases are a major problem in advanced breast cancer, most of the damage being mediated by the stimulation of osteoclasts by tumour derived cytokines. Important advances in treatment have come from the use of bisphosphonates and beta emitting isotopes. Monitoring of bone metastases is enhanced by using biochemical parameters of response in addition to imaging techniques.
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PMID:Improving treatment for advanced breast cancer. 801 92

The place of tamoxifen in the treatment of metastatic breast cancer is being challenged by the development of less estrogenic antiestrogens. New inhibitors of aromatase and estrone sulfatase have been reported. Anthrapyrazoles are new cytotoxic agents with high activity and low toxicity. Uncertainty about the optimal duration of chemotherapy continues. Methods to intensify chemotherapy, enabled by bone marrow support techniques, continue to be studied, but a routine role for this approach in palliative treatment of metastatic disease has not been established. Active specific immunotherapy appears to be practicable following identification of defined tumor-associated immunogens. Evidence for the ability of bisphosphonates to reduce morbidity from bone metastases continues to accumulate.
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PMID:Metastatic breast cancer. 830 49

Bone metabolism marker evaluation is expected to play an auxiliary role in the diagnosis and follow-up of bone metastases in patients affected by different types of neoplasms. In this study we have evaluated osteoblastic and osteoclastic markers in 18 patients with bone metastases from breast cancer at diagnosis and for 1 year of follow-up during treatment with the aromatase inhibitor formestane. Osteoblastic markers include the carboxy-terminal propeptide of type I procollagen, the bone-specific alkaline phosphatase and the bone GLA protein. The carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) was evaluated as a marker of osteoclastic activity. The patients were classified into three groups according to clinical response. A good correlation between marker level modifications and clinical evolution of skeletal metastases was observed for all the examined markers. Patients with progressive disease showed increasing levels of all markers, whereas patients in regression showed a reduction compared to the basal levels; patients with stable disease fell in between these two categories. We also found that basal ICTP values have prognostic significance: in the stable and progressive disease group they were higher than in the partial response group.
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PMID:Serum markers of bone metastases in postmenopausal breast cancer patients treated with formestane. 921 4

A significant percentage (50-70%) of patients with metastatic breast carcinoma (MBC) will have disease involving the bony skeleton. Clonal selection mediated by parathyroid hormone-related protein and other factors may explain the high incidence of osseous metastases in MBC. The presence of specific growth factors and cytokines in the microenvironment of bone may contribute to the successful establishment and growth of metastatic lesions and also might determine response or resistance of these lesions to chemotherapy or hormonal therapy. Osteolytic bone lesions in MBC frequently give rise to serious clinical problems including bone pain, pathologic fracture, hypercalcemia, and neurologic complications. MBC often is treated with systemic chemotherapy or hormonal therapy. The purpose of this article was to review the recent published literature describing the impact of systemic chemotherapy and hormonal therapy of MBC on the response of bone lesions and their clinical course and complications. Evaluating the response of bone lesions can be problematic and may be complicated by the phenomenon of "tumor flare" that may be observed with either chemotherapy or hormonal therapy. Use of the International Union Against Cancer criteria for the response of bone lesions is recommended. Several studies report objective responses (20-60%) of lytic bone metastases to standard combination chemotherapy regimens such as cyclophosphamide, methotrexate, and 5-fluorouracil and cyclophosphamide, doxorubicin, and 5-fluorouracil, mitoxantrone and 5-FU, newer combinations, and single agents including paclitaxel and docitaxel but responses to vinorelbine may be less frequent. Complete responses of bone lesions to chemotherapy are rare but partial responses and disease stabilization can lead to long term patient benefit. A series from the M. D. Anderson Cancer Center of patients with bone metastases treated with 5-FU, doxorubicin, and cyclophosphamide chemotherapy reported a median duration of response of 14 months. In a recent multicenter study of 195 patients with lytic lesions from MBC treated with chemotherapy, the objective response rate (complete response + partial response) in bone was 18% and 65% of the patients developed at least 1 morbid skeletal event with a median onset of 7.0 months from the start of chemotherapy. Hormone-dependent breast carcinoma has a proclivity to metastasize to bone. In earlier studies comparing aminoglutethimide or medroxyprogesterone acetate with tamoxifen, a higher response rate of bone metastases was observed for the first two agents. However, in more recent studies comparing newer aromatase inhibitors, such as anastrozole, fadrozole, and letrozole, with megestrol acetate, there were no significant differences in rates of response in bone. Patients with MBC with bony lesions respond to both chemotherapy and hormonal therapy and can have a prolonged survival. Therefore such patients are in a more favorable position to benefit from adjunctive supportive therapy such as bisphosphonates intended to reduce skeletal morbidity.
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PMID:Issues concerning the role of chemotherapy and hormonal therapy of bone metastases from breast carcinoma. 936 31

This Phase II study was designed to determine the efficacy and tolerability of vorozole (R83842), a new nonsteroidal aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression being treated with tamoxifen, and to correlate these effects with the hormonal profile and plasma drug levels. Twenty-nine eligible women with estrogen receptor-positive or unknown disease were treated with 2.5 mg vorozole once daily p.o. until disease progression. All 29 are evaluable for toxicity and 27 for response as assessed by International Union Against Cancer (UICC) criteria. After a median follow-up of 8 months, 3 patients (11%) had partial remission of their disease for 14, 15, and 16 months and 14 patients had disease stabilization for 7-24 months (median, 12). Patients with a normal carcinoembryonic antigen level (</=3 mm/liter), those without bone metastases, older women, and those with a long disease-free interval were most likely to benefit from treatment. Estradiol decreased from pretreatment levels of 9. 2-85 pm/liter (mean, 24) to below detection (9.2 pm/liter) and estrone from 64-311 pm/liter (mean, 144.3) to 19-116 pm/liter (mean, 57) after 1 month. Serum follicle-stimulating and luteinizing hormone levels rose from 9-74 IU/liter (mean, 35.3) and 3.3-38 IU/liter (mean, 17.8) to 10-102 IU/liter (mean, 44.6) and 1.6-70 IU/liter (mean, 24.2) and sex hormone-binding globulin fell from 27-138 nm/liter (mean, 65.4) to 15-109 nm/liter (mean, 53.8) after 1 month of treatment. Corresponding levels of androstenedione, dehydroepiandrosterone, free testosterone, and 17alpha-hydroxyprogesterone were unaffected. An adrenocorticotropic hormone stimulation test was normal in 18 patients 1 month after treatment commenced. Trough drug levels (measured by gas chromatography) ranged from 6.5-95 ng/ml (median, 24.5) at 1 month of treatment. Possible treatment-related side effects were mild and included malaise, anorexia and nausea, hot flashes, fluid retention, vaginal infection, alopecia, lightheadedness, and one allergic reaction which caused lip swelling. Vorozole, given orally, is a clinically active well-tolerated new treatment for breast cancer. Selective suppression of estrogen confirms its action as a specific aromatase inhibitor. Further trials to confirm its relative efficacy in postmenopausal disease and to explore its application in other settings are indicated.
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PMID:Phase II study of vorozole (R83842), a new aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression on tamoxifen. 981 84

Adjuvant systemic treatments have greatly improved the prognosis of women with early breast cancer. Combination chemotherapy and, for patients with oestrogen receptor-positive (ER+) tumours, endocrine treatment has been found to reduce the frequency of relapse and improve survival. New adjuvant strategies include the introduction of taxanes into adjuvant chemotherapy schedules, the use of aromatase inhibitors in place of, or in addition to, tamoxifen, and the use of adjuvant bisphosphonates. Combination chemotherapy has been found to reduce the annual odds of recurrence and death in pre- and postmenopausal women. The benefits, however, are on average less in older patients. Anthracycline-based regimens are more effective than traditional regimens of cyclophosphamide, methotrexate, and fluorouracil (CMF). The benefits of adjuvant cytotoxic and endocrine treatments are additive. There is considerable debate as to the role of taxanes in adjuvant therapy. Improved outcome has been observed in one large trial, especially in those patients with ER-negative tumours. High-dose chemotherapy has not fulfilled its early promise. Ovarian suppression and/or tamoxifen remain the treatments of choice. The annual odds of relapse and death have been reduced by approximately one-third and one-quarter, respectively. Several very large studies are in progress to assess the potential of aromatase inhibitors in the adjuvant setting. Direct comparisons with tamoxifen, as well as switching after several years from tamoxifen to an aromatase inhibitor, are strategies under evaluation. Early results from one of these trials evaluating anastrozole (the Arimidex, Tamoxifen, Alone or in Combination [ATAC] trial) has reported a reduced relapse rate after a median follow-up of 3 years in favour of anastrozole. However, this was at the expense of accelerated bone loss, and strategies to minimise this side effect of aromatase inhibitors are under investigation. Although many studies have indicated that bisphosphonates prevent the development of metastatic bone disease in animals, the clinical role of prophylactic bisphosphonates in early breast cancer is not clearly defined. Three studies with oral clodronate have been published, two of them indicating a protective effect on the development of bone metastases and improved survival, and one suggesting a disadvantage to the use of adjuvant clodronate. Further large adjuvant trials with clodronate and zoledronic acid are in progress. Adjuvant bisphosphonates also have been found to reduce bone loss associated with cancer treatments and preserve skeletal health. It may be possible to replace the current oral regimens for prevention of bone loss with a single annual infusion of the highly potent bisphosphonate zoledronic acid.
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PMID:Current and future status of adjuvant therapy for breast cancer. 1254 90

Endocrine therapy remains important in the adjuvant treatment of pre- and postmenopausal women. Adjuvant ovarian ablation with or without tamoxifen produces effects which are equivalent to those of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in premenopausal women with oestrogen receptor (ER) and/or progesterone receptor (PgR) positive breast cancer. Tamoxifen alone is also effective in these women. Concurrent use of tamoxifen and ovarian ablation may be even more effective, but more studies are needed. Tamoxifen remains a standard adjuvant therapy for postmenopausal women with ER and/or PgR positive tumours. Current information supports the use of 5 years of tamoxifen but additional studies comparing 5 years to longer duration are ongoing. The aromatase inhibitor (AI) anastrozole has now been demonstrated to be better than tamoxifen in preventing recurrence in early reports from the Arimidex vs Tamoxifen And the Combination (ATAC) Trial. Ongoing trials of this and other AIs before, after, concurrent with, or substituted for tamoxifen in the adjuvant setting may soon revolutionize our approach for postmenopausal women. Adjuvant bisphosphonates have been shown to reduce the incidence of bone metastases and improve survival in two of three published adjuvant trials and are being further studied. Her-2 neu status is being explored as a predictive factor for selection of endocrine therapy, but is not yet considered standard for this purpose.
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PMID:The best use of adjuvant endocrine treatments. 1465 27

Tamoxifen is the standard first-line endocrine therapy for breast cancer, but recent data indicate that it is likely to be replaced by the effective aromatase inhibitors (AIs), in both the metastatic and adjuvant settings. Aromatase inhibitors induce complete oestrogen deprivation that leads to clinically significant bone loss. Several ongoing or planned trials combine AIs with bisphosphonates, even more so that recent data reveal that clodronate may reduce the incidence of bone metastases and prolong survival in the adjuvant setting. Bisphosphonates can inhibit breast cancer cell growth in vitro, but they have never been studied in steroid-free medium (SFM), an in vitro environment that mimics the effects of AIs in vivo. Quite surprisingly, in SFM, clodronate stimulated MCF-7 cell growth in a time- and dose-dependent manner by up to two-fold (crystal violet staining assay), whereas it had no mitogenic activity in complete medium. The bisphosphonate similarly increased the proliferation of IBEP-2 cells, which also express a functional oestrogen receptor (ER), while it weakly inhibited the growth of the ER-negative MDA-MB-231 cells. Expectedly, 17beta-oestradiol stimulated the growth of MCF-7 and IBEP-2 cells cultured in SFM, and had no effect on MDA-MB-231 cells. Moreover, partial (4-OH-tamoxifen) and pure antioestrogens (fulvestrant, ICI 182,780), in combination with clodronate, completely suppressed the mitogenic effect of the bisphosphonate, suggesting that it was mediated by an activation of ER. In accordance with this view, clodronate induced ER downregulation, weakly increased progesterone receptor expression, and stimulated the transcription of an oestrogen-responsive reporter gene. In conclusion, we report a previously unknown stimulatory effect of clodronate on MCF-7 cells grown in SFM, in vitro conditions that are potentially relevant to the use of AIs for breast cancer. Moreover, our data suggest that ER is involved in these effects of clodronate on cancer cell growth.
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PMID:Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells. 1547 66


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