Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is an antiestrogen frequently used in the treatment of breast cancer and is currently being assessed as a prophylactic for those at high risk of developing tumors. We have found that tamoxifen and its derivatives are high-affinity blockers of specific chloride channels. This blockade appears to be independent of the interaction of tamoxifen with the estrogen receptor and therefore reflects an alternative cellular target. One of the clinical side effects of tamoxifen is impaired vision and cataract. Chloride channels in the lens of the eye were shown to be essential for maintaining normal lens hydration and transmittance. These channels were blocked by tamoxifen and, in organ culture, tamoxifen led to lens opacity associated with cataracts at clinically relevant concentrations. These data suggest a molecular mechanism by which tamoxifen can cause cataract formation and have implications for the clinical use of tamoxifen and related antiestrogens.
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PMID:Tamoxifen blocks chloride channels. A possible mechanism for cataract formation. 792 48

Breast cancer is the most frequent female malignant disease in developed countries. Various approaches are being developed for breast cancer prevention. Medical prevention called chemoprevention is reviewed. Prior to any intervention estimation of breast cancer risk is mandatory. For practical reasons distinction of two risk groups is useful. In the high risk group inherited gene mutation showing high penetrance may be suspected, while in the medium risk group hormonal factors play an important role. The antiestrogen tamoxifen has been extensively investigated in breast cancer and also tested for the prevention of breast cancer. The results of four randomized tamoxifen prevention studies have been published. In the largest, American trial the number of invasive or "in situ" breast cancers was halved by tamoxifen. Particularly estrogen receptor positive and relatively good prognosis breast cancers were reduced. Similar results were obtained in the "International Breast Intervention Study". Tamoxifen has been registered for breast cancer prevention for high risk individuals in the United States. The Italian and English ("Royal Marsden Hospital") studies did not prove significant preventative effect for tamoxifen that may be explained by the characteristics of the study protocols and study populations. Increased rates of endometrial cancer, thromboembolic events and cataract were observed under tamoxifen treatment, especially over the age of 50. Prevention has an increased importance in gene mutation carriers. Besides prophylactic mastectomy and close surveillance tamoxifen and bilateral oophorectomy or the use of gonadotropin releasing-hormone analogs seem efficient in this group. Various new chemoprevention strategies are under testing. Raloxifene and the aromatase inhibitors show advantage in menopausal women, the retinoid fenretinide and the gonadotropin releasing-hormone analogs seem promising for premenopausal individuals. The use of these agents are investigated in clinical trials. It is likely that not one single method will be applied for breast cancer prevention in the future. Preferably individual prevention strategies based on individual risk assessment will be developed.
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PMID:[Breakthrough in breast cancer chemoprevention]. 1272 84

Actin filaments play a critical role in the normal physiology of lenticular and retinal cells in the eye. Disruption of the actin cytoskeleton has been associated with retinal pathology and lens cataract formation. Ocular toxicity is an infrequent observation in drug safety studies, yet its impact to the drug development process is significant. Recognizing compounds through screening with a potential ocular safety liability is one way to prioritize development candidates while reducing development attrition. Lens epithelial cells from human, dog, and rat origins and retinal pigmented epithelium cells from human, monkey, and rat origins were cultured and investigated with immunocytochemical techniques. Cells were treated using noncytotoxic doses of the compound, fixed, stained for actin with rhodamine phalloidin, and counterstained for nuclei with TOTO-3, followed by confocal imaging. Tamoxifen and several experimental compounds known to be in vivo lens and retinal toxicants caused a reduction in F-actin fluorescence at noncytotoxic concentrations in all cells tested as observed by confocal microscopy. Developing an assay that predicts ocular toxicity helps the development process by prioritizing compounds for further investigation. Drug-induced cytoskeletal alterations may be useful as a potential safety-screening marker of retinal and lens toxicity. The knowledge of actin molecular biology and the application of other mechanistic screens to toxicology are discussed. Reducing this work to a high-throughput platform will enable chemists to select compounds with a reduced risk of ocular toxicity.
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PMID:Investigating cytoskeletal alterations as a potential marker of retinal and lens drug-related toxicity. 1719 8

Tamoxifen and raloxifene are both selective estrogen receptor modulators (SERMs). The medicines can block estrogen mediated breast cancer growth and development but will also maintain bone density in postmenopausal women and lower circulating cholesterol. Tamoxifen has remained the antihormonal therapy of choice for the treatment of ER positive breast cancer for the last 30 years. However, although adjuvant tamoxifen produces profound increases in disease-free and overall survival in patients with ER positive breast cancer, concerns about drug resistance, blood clots and endometrial cancer have resulted in a change to the use of aromatase inhibitors for the treatment of postmenopausal women. Nevertheless, tamoxifen remains the antihormonal treatment of choice for premenopausal women with ER positive breast cancer and for risk reduction in premenopausal women who are at high risk for developing breast cancer. The risk of endometrial cancer and thromboembolic disorders during tamoxifen therapy is not elevated in premenopausal women. It is important to note that aromatase inhibitors or raloxifene should not be used in premenopausal women. Raloxifene is used to prevent osteoporosis in postmenopausal women and, unlike tamoxifen, does not increase the risk of endometrial cancer. However, raloxifene does reduce breast cancer risk by 50-70% in both low risk and high risk postmenopausal women. Comparisons of raloxifene with tamoxifen show equal efficacy as a chemopreventive for breast cancer but there is a reduction in thromboembolic disorders, fewer endometrial cancers, hysterectomies, cataracts and cataract surgeries in women taking raloxifene. Overall, SERMs continue to fulfill their promise as appropriate medicines that target specific populations for the treatment and prevention of breast cancer.
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PMID:SERMs for the treatment and prevention of breast cancer. 1744 Aug 19

In the Study of Tamoxifen and Raloxifene (STAR) trial, postmenopausal women at increased risk of breast cancer received either oral tamoxifen (20 mg/day) or raloxifene (60 mg/day) over 5 years. There were an equal number of cases of invasive breast cancer in women assigned to tamoxifen and raloxifene. There were fewer cases of noninvasive breast cancer in the tamoxifen group than in the raloxifene group (risk ratio [RR]: 1.40; 95% confidence interval [CI]: 0.98-2.02). There were more cases of uterine cancer with tamoxifen than with raloxifene (RR: 0.62; 95% CI: 0.35-1.08). Thromboembolic events occurred less often in the raloxifene group (RR: 0.70; 95% CI: 0.54-0.91) and there were fewer cataracts and cataract surgeries in the women taking raloxifene (RR: 0.79; 95% CI: 0.68-0.92). The STAR trial has shown that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of adverse events but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease and stroke is similar for both drugs.
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PMID:The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. 1910 6

This review concerns the effects on vision and the eye of medications prescribed at three phases of treatment for women with early-stage breast cancer (BC): (1) adjuvant cytotoxic chemotherapy, (2) adjuvant endocrine therapy, and (3) symptomatic relief. The most common side effects of cytotoxic chemotherapy are epiphora and ocular surface irritation, which can be caused by any of several different regimens. Most notably, the taxane docetaxel can lead to epiphora by inducing canalicular stenosis. The selective-estrogen-receptor-modulator (SERM) tamoxifen, long the gold-standard adjuvant-endocrine-therapy for women with hormone-receptor-positive BC, increases the risk of posterior subcapsular cataract. Tamoxifen also affects the optic nerve head more often than previously thought, apparently by causing subclinical swelling within the first 2 years of use for women older than ~50 years. Tamoxifen retinopathy is rare, but it can cause foveal cystoid spaces that are revealed with spectral-domain optical coherence tomography (OCT) and that may increase the risk for macular holes. Tamoxifen often alters the perceived color of flashed lights detected via short-wavelength-sensitive (SWS) cone response isolated psychophysically; these altered perceptions may reflect a neural-response sluggishness that becomes evident at ~2 years of use. The aromatase inhibitor (AI) anastrozole affects perception similarly, but in an age-dependent manner suggesting that the change of estrogen activity towards lower levels is more important than the low estrogen activity itself. Based on analysis of OCT retinal thickness data, it is likely that anastrozole increases the tractional force between the vitreous and retina. Consequently, AI users, myopic AI users particularly, might be at increased risk for traction-related vision loss. Because bisphosphonates are sometimes prescribed to redress AI-induced bone loss, clinicians should be aware of their potential to cause scleritis and uveitis occasionally. We conclude by suggesting some avenues for future research into the visual and ocular effects of AIs, particularly as relates to assessment of cognitive function.
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PMID:Breast cancer medications and vision: effects of treatments for early-stage disease. 2181 59