Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is now established for use in premenopausal as well as postmenopausal patients. Recent reports have not shown its activity to be enhanced by the addition of either prednisolone, progestogens, or interferon. Reversible ocular toxicity from tamoxifen appears to be more common than had been previously realized. Different schedules giving the same dose intensity of doxorubicin give markedly different pharmacokinetic profiles. Although this does not lead to differences in responses or physical toxicity, it seems to have important implications for quality of life. Taxol is showing impressive activity in advanced breast cancer, and significant response rates have also been reported for carboplatin and podophyllotoxin derivatives. To achieve maximum effectiveness from the cyclophosphamide, methotrexate, and fluorouracil combination, attention to schedule and dose intensity has been shown to be important. No new effective cytotoxic combinations have been described. High-dose chemotherapy requiring bone marrow support remains experimental. Further progress has been made in monitoring the response of metastatic bone disease to treatment. The precise significance for patients of the results in many of the papers reviewed is often uncertain because they lack quality-of-life measures; the importance of this approach is emphasized.
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PMID:Metastatic breast cancer and its complications. 145 19

Postmenopausal osteoporosis, the most common bone disease in the developed world, is associated with estrogen deficiency. This deficiency induces increased generation and activity of osteoclasts, which perforate bone trabeculae, thus reducing their strength and increasing fracture risk. Estrogen replacement prevents these effects, indicating that estrogen negatively regulates osteoclast formation and function, but how it does this is unclear. Because functional osteoclast life span and thus the amount of bone that osteoclasts resorb could also be enhanced following estrogen deficiency, and since sex steroids regulate apoptosis in other target tissues, we investigated whether estrogen may affect osteoclast function by promoting apoptosis. 17 beta-Estradiol promoted apoptosis of murine osteoclasts in vitro and in vivo by two- to threefold. Tamoxifen, which has estrogenic effects on bone resorption, and transforming growth factor-beta 1 (TGF-beta), whose production by osteoblasts is increased by estrogen, had similar effects in vitro. Anti-TGF-beta antibody inhibited TGF-beta-, estrogen- and tamoxifen-induced osteoclast apoptosis, indicating that TGF-beta might mediate this effect. These findings suggest that estrogen may prevent excessive bone loss before and after the menopause by limiting osteoclast life span through promotion of apoptosis. The development of analogues to promote this mechanism specifically could be a useful and novel therapeutic approach to prevent postmenopausal osteoporosis.
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PMID:Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. 883 13

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

Breast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four of CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. The taxanes have been approved for adjuvant therapy in the USA, while European approval is pending. Combined endocrine-chemotherapy is the standard adjuvant treatment in high-risk patients with endocrine-responsive tumours. Endocrine manipulation is usually administered after completion of the chemotherapy programme. For HER2-neu overexpressing tumours, several rapidly accruing trials are exploring the potential additive effect of trastuzumab, a monoclonal antibody directed against the extramembrane portion of the HER2 receptor. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer, with increased rates of breast-conserving surgery. A proportion of patients achieve a pathological complete response and these patients have significantly better long-term outcomes. Twenty-five to forty percent of breast cancer patients develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In the case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure anti-oestrogens and progestins. Aromatase inhibitors are the most active agents, but the choice and the sequence of endocrine therapies are also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in cases of receptor-negative tumours, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation, and this approach should be recommended in young patients with good performance status and visceral disease. On the other hand, single agents have a better tolerability profile and should be tand should be the treatment of choice when a careful balance between activity and tolerability is needed. For HER2-neu positive tumours, the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone in terms of both response rates and survival. Other useful palliative treatments include bisphosphonates for the control of metastatic bone disease and radiotherapy for painful bone lesions or local relapses.
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PMID:The curability of breast cancer and the treatment of advanced disease. 1510 48

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.
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PMID:Endocrine therapy of breast cancer. 2114 13