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At least 55 records · Page 3Linked to original sources
PubMed2003

Effects of hydroxyapatite nanoparticles on proliferation and apoptosis of human hepatoma BEL-7402 cells.

AIM: To study the effect of hydroxyapatite (HAP) nanoparticles on human hepatoma cell line BEL-7402 in vitro. METHODS: The human hepatoma cell line BEL-7402 was cultured and treated with HAP nanoparticles at various concentrations. Growth suppression was detected with MTT colorimetric assay, cell apoptotic alterations were evaluated by cytochemical staining (Hoechst 33258), transmission electron microscopy (TEM), and flow cytometry (FCM). RESULTS: HAP nanoparticles inhibited the growth of hepatoma cells in a dose-dependent manner, with IC(50) values of 29.30 mg/L. Treated with 50-200 mg/L HAP nanoparticles for 48 h, BEL-7402 cells apoptosis with nuclear chromatin condensation and fragmentation as well as cell shrinkage and the formation of apoptotic bodies were observed under cytochemical staining and transmission electron microscopy. FCM analysis showed hypodiploid peaks on histogram, the apoptotic rates at the concentrations of 50, 75, 100, 150 and 200 mg/L of HAP nanoparticles were 20.35+/-2.23 %, 25.35+/-1.92 %, 29.34+/-4.61 %, 44.92+/-3.78 % and 53.64+/-3.49 %, respectively, which were all significantly higher than that of control group 2.23+/-0.14 %. There was a significant correlation between HAP nanoparticle concentration and apoptotic rate (r=0.994, P<0.01). CONCLUSION: HAP nanoparticles not only inhibit proliferation but also induce apoptosis of human hepatoma cell line BEL-7402 in vitro.

Antineoplastic Agents↗
PubMed2001

Antineoplastic mechanism of Octreotide action in human hepatoma.

OBJECTIVES: To investigate whether apoptosis can be induced by Octreotide in human hepatoma cells in vitro and elucidate the antineoplastic mechanism of Octreotide in hepatoma. METHODS: A cultured human hepatoma cell line, BEL-7402, was exposed to Octreotide and apoptosis was evaluated by cytochemical staining (Hochesst 33,258), transmission electron microscopy, agarose gel electrophoresis and flow cytometry (FCM). RESULTS: After exposure to 0.2 microgram/ml Octreotide, apoptosis with nuclear chromatin condensation as well as fragmentation, cell shrinkage and the formation of apoptotic bodies was observed using cytochemical staining and transmission electron microscopy. A DNA ladder in agarose gel electrophoresis was also displayed. FCM showed that the apoptotic cell number rose with an increase in the concentration of Octreotide (0-2 micrograms/ml). There was a positive correlation between Octreotide concentration and apoptotic rate in BEL-7402 cells (r = 0.809, P < 0.05). CONCLUSION: Apoptosis in human hepatoma cells can be induced by Octreotide, which may be related to the mechanism of antineoplastic action of Octreotide in hepatoma.

Antineoplastic Agents, Hormonal↗
PubMed2003

A comparison of the efficacy of aromatase inhibitors in second-line treatment of metastatic breast cancer.

Randomized clinical trials have established the role of third-generation aromatase inhibitors (AIs) (letrozole, anastrozole, and exemestane) as standard treatment for patients with hormone-sensitive metastatic breast cancer who have experienced disease progression with antiestrogen therapy. Significant gains in clinical efficacy and improved tolerability over progestins (megestrol acetate) and the first-generation AI aminoglutethimide have positioned these agents above previous therapies. Estrogen receptor (ER) status remains the best predictive determinant of endocrine response, and further randomized trials with properly selected patient populations may distinguish individual AIs within this class. A recently completed, randomized, head-to-head phase III trial of letrozole versus anastrozole as second-line endocrine therapy demonstrated a significant difference in objective response rate for letrozole compared with anastrozole (19% versus 12%, respectively; P = 0.014), with similar time to progression. The improved efficacy and safety of AIs as second-line endocrine therapies has spawned trials of their use as first-line endocrine therapy versus tamoxifen for patients with metastatic breast cancer. Based on favorable results from these trials, letrozole and anastrozole have also been approved for use as first-line treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer.

Aminoglutethimide↗
PubMed2004

Effect of curcumin on normal and tumor cells: role of glutathione and bcl-2.

Curcumin, a well-known dietary pigment derived from Curcuma longa, inhibited growth of several types of malignant cells both in vivo and in vitro. However, its mechanism of action still remains unclear. In this study, we have focused primarily on the cytotoxic effects of curcumin on three human tumor cell lines and rat primary hepatocytes. Curcumin induced apoptosis in MCF-7, MDAMB, and HepG2 cells in a dose-dependent and time-dependent manner. Apoptosis was mediated through the generation of reactive oxygen species. Attempts were made to establish the role played by endogenous glutathione on the apoptotic activity of curcumin. Depletion of glutathione by buthionine sulfoximine resulted in the increased generation of reactive oxygen species, thereby further sensitizing the cells to curcumin. Interestingly, curcumin had no effect on normal rat hepatocytes, which showed no superoxide generation and therefore no cell death. These observations suggest that curcumin, a molecule with varied actions, could be developed into an effective chemopreventive and chemotherapeutic agent.

Antineoplastic Agents↗
PubMed2006

Estrogen receptors as therapeutic targets in breast cancer.

The estrogen receptor alpha (ERalpha) has proven to be the single most important target in breast cancer over the last 30 years. The use of the selective ER modulator (SERM) tamoxifen for the treatment and prevention of breast cancer has changed therapeutics. The SERM raloxifene, approved for the treatment of osteoporosis, lacks tamoxifen's increased risk for endometrial cancer and is being evaluated for the prevention of breast cancer. Other SERMs approved or under development for use against breast cancer or osteoporosis include toremifene, GW5638, GW7604 (the active metabolite of GW5638), idoxifene, lasofoxifene, arzoxifene, bazedoxifene, EM-800 and acolbifene (the active metabolite of EM-800). Aromatase inhibitors (AIs) have recently proven to be more efficacious than tamoxifen as first-line therapy, efficacious for second-line therapy (e.g. against tamoxifen-resistant disease), and useful for extended adjuvant therapy after tamoxifen. The AIs include the non-steroidal agents letrozole and anastrole, and the steroidal agent exemestane. The pure antiestrogen fulvestrant has proven to be just as effective as AIs. Other pure antiestrogens, ZK-703, ZK-253, RU 58668 and TAS-108 show great promise. The development of resistance to endocrine therapy remains a clinically important problem, and laboratory models based on human breast cancer cells grown as tumors in immune-compromised mice have led to important insights into this problem. Progesterone receptor-negative status of ER-positive breast cancers may reflect altered growth factor receptor signaling, and helps to explain why this subclass of tumors exhibits lower response rates to tamoxifen compared to cancers typed progesterone receptor-positive. Crosstalk among plasma membrane-localized ER, growth factor receptor signaling, and nuclear-localized ER provide further insights into antihormonal-resistant breast cancer.

Animals↗
PubMed1976

Prolongation of allograft survival by combination therapy with anti-thymocyte serum and anti-immunoglobulin.

Heterologous anti-immunoglobulin (AI) is a potent immunosuppressive agent which compares favorably to anti-thymocyte serum (ATS) in inhibiting E and EAC-rosette formation and diminishing the secondary antibody response to sheep erythrocytes and E. coli lipopolysaccharide. AI prolongs H-2 incompatible skin allograft survival than either antiserum used alone, without evidence of toxicity to recipient mice. AI does not cause significant immune complex glomerular or renovascular deposition and may act by interference with antigen binding.

Animals↗
PubMed2005

Sequencing of aromatase inhibitors.

Since the development of the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, these agents have been the subject of intensive research to determine their optimal use in advanced breast cancer. Not only have they replaced progestins in second-line therapy and challenged the role of tamoxifen in first-line, but there is also evidence for a lack of cross-resistance between the steroidal and nonsteroidal AIs, meaning that they may be used in sequence to obtain prolonged clinical benefit. Many questions remain, however, as to the best sequence of the two types of AIs and of the other available agents, including tamoxifen and fulvestrant, in different patient groups.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line.

Androgen receptor (AR) overexpression is one of the characteristics of prostate cancer (PC) that progresses to hormone independence. An androgen-independent (AI) derivative, with much higher AR-mRNA and protein levels than the parental LNCaP cell line, whose proliferation was androgen dependent (AD), was used to explore the mechanism of AR overexpression. We found that a suppressor element (ARS), previously identified in mouse AR and located in the 5'-untranslated region of human AR gene, malfunctions in AI cells. Transfection of constructs that included ARS element into AD cells reduced the transactivating activities of both AR promoter and a heterologous SV40 promoter. The deletion of ARS resulted in an eightfold increase in AR-promoter activity in AD cells, but had no effect in AI cells. Moreover, the nuclear extracts of AD cells contained proteins that produced a specific, ARS-binding complex, while this complex appeared to have been lost from AI cells. Most importantly, treatment of AI cells with a demethylating agent or histone deacetylase inhibitors restored the lost ARS-binding complex. The restoration of the complex coincided with a reduced expression of AR-mRNA and protein and a reduced rate of AR-gene transcription, determined by nuclear run-on experiment. Thus, epigenetic transcriptional silencing of the suppressor protein(s) may be responsible for AR overexpression in AI cells, and its reversal in hormone-independent PC may normalize AR levels and restore their hormone dependence.

5' Untranslated Regions↗
PubMed2005

Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study.

OBJECTIVE: To determine the prevalence, time course, clinical characteristics, and effect of adrenal insufficiency (AI) after traumatic brain injury (TBI). DESIGN: Prospective intensive care unit-based cohort study. SETTING: Three level 1 trauma centers. PATIENTS: A total of 80 patients with moderate or severe TBI (Glasgow Coma Scale score, 3-13) and 41 trauma patients without TBI (Injury Severity Score, >15) enrolled between June 2002 and November 2003. MEASUREMENTS: Serum cortisol and adrenocorticotropic hormone levels were drawn twice daily for up to 9 days postinjury; AI was defined as two consecutive cortisols of < or =15 microg/dL (25th percentile for extracranial trauma patients) or one cortisol of < 5 microg/dL. Principal outcome measures included: injury characteristics, hemodynamic data, usage of vasopressors, metabolic suppressive agents (high-dose pentobarbital and propofol), etomidate, and AI status. MAIN RESULTS: AI occurred in 42 TBI patients (53%). Adrenocorticotropic hormone levels were lower at the time of AI (median, 18.9 vs. 36.1 pg/mL; p = .0001). Compared with patients without AI, those with AI were younger (p = .01), had higher injury severity (p = .02), had a higher frequency of early ischemic insults (hypotension, hypoxia, severe anemia) (p = .02), and were more likely to have received etomidate (p = .049). Over the acute postinjury period, patients with AI had lower trough mean arterial pressure (p = .001) and greater vasopressor use (p = .047). Mean arterial pressure was lower in the 8 hrs preceding a low (< or =15 microg/dL) cortisol level (p = .003). There was an inverse relationship between cortisol levels and vasopressor use (p = .0005) and between cortisol levels within 24 hrs of injury and etomidate use (p = .002). Use of high-dose propofol and pentobarbital was strongly associated with lower cortisol levels (p < .0001). CONCLUSIONS: Approximately 50% of patients with moderate or severe TBI have at least transient AI. Younger age, greater injury severity, early ischemic insults, and the use of etomidate and metabolic suppressive agents are associated with AI. Because lower cortisol levels were associated with lower blood pressure and higher vasopressor use, consideration should be given to monitoring cortisol levels in intubated TBI patients, particularly those receiving high-dose pentobarbital or propofol. A randomized trial of stress-dose hydrocortisone in TBI patients with AI is underway.

Acute Disease↗
PubMedDate not supplied

Aromatase inhibitors as adjuvant therapy for postmenopausal patients with early stage breast cancer.

Endocrine therapy of hormone receptor-positive breast tumors is widely used as palliative therapy for metastatic breast cancer and as adjuvant therapy for early stage breast cancer. Tamoxifen has been the definitive standard of hormonal therapies for the last 30 years because of its documented efficacy and reasonable safety profile. Based on encouraging results from trials utilizing the selective, third generation aromatase inhibitors (AIs) in metastatic breast cancer, a number of trials were designed to examine these agents as adjuvant therapies. Trials directly comparing AIs with tamoxifen have, to date, demonstrated superior disease-free-survival with AIs. Likewise, trials examining the use of AIs after tamoxifen have demonstrated better outcomes compared with tamoxifen alone. Additionally, letrozole has been demonstrated to result in superior disease-free-survival after 5 years of adjuvant tamoxifen, compared with no further therapy. In general, the AIs are tolerated at least as well as tamoxifen but decrease bone mineral density and increase osteoporosis due to their lack of estrogenic effects on bone. Based on the fact that AIs appear more effective at preventing contralateral breast cancers than tamoxifen, they are being examined as breast cancer preventives. Despite available data using the AIs as adjuvant therapies, many questions remain unanswered, and further trials will be needed to address these important issues.

Aromatase Inhibitors↗
PubMed2002

HER-2 profiling and targeting in prostate carcinoma.

BACKGROUND: The clinical effects of targeting HER-2 in prostate carcinoma are not known. This study explored the feasibility of molecular profiling to determine the correlation between HER-2 expression, hormonal sensitivity, and the antitumor effects of trastuzumab and paclitaxel in patients with prostate carcinoma. METHODS: Patients with progressive androgen dependent (AD) and androgen independent (AI) prostate carcinoma were eligible to participate in the study. HER-2 expression was assessed on pretreatment tissue specimens, and patients were then assigned to one of four treatment groups: AD HER-2 positive, AD HER-2 negative, AI HER-2 positive, and AI HER-2 negative. They were treated with weekly trastuzumab at a dose of 2 mg/kg (after a 4 mg/kg loading dose) until they experienced disease progression, when weekly paclitaxel at 100 mg/m(2) was added. RESULTS: The authors screened 130 patients for HER-2 expression. In total, 23 patients were treated. Six eligible patients had HER-2 positive disease; therefore, only the AI HER-2 negative arm accrued to completion. All patients (100%) experienced disease progression on trastuzumab alone at or before the first 12 weeks of treatment. Fifteen patients received combined therapy: Seven patients (47%) experienced disease progression, 5 patients (33%) had stable disease, and 3 patients (20%) had a decline > or = 50% in prostate specific antigen PSA level or in soft tissue disease. HER-2 overexpression was found in significant proportions only in AI metastatic tissue samples (42% HER-2 positive; 95% confidence interval, 14-60%). In three of nine matched pairs, the AD prostate biopsy was HER-2 negative, and the AI metastatic sample was HER-2 positive. CONCLUSIONS: Trastuzumab is not effective as a single agent for the treatment of patients with AI HER-2 negative tumors. HER-2 expression varies by clinical state in patients with prostate carcinoma: Accurate HER-2 profiling requires sampling metastatic tissue in patients with metastatic disease. Further development of trastuzumab for the treatment of patients with metastatic prostate carcinoma is not feasible until more reliable and practical methods of sampling metastatic disease are developed to identify patients with HER-2 positive tumors.

Aged↗
PubMed2007

In vitro and in vivo anti-tumor effects of Astragalus membranaceus.

Astragalus membranaceus, a commonly used Chinese medicinal plant, has been shown to be capable of restoring the impaired T cell functions in cancer patients. In this study, the in vitro and in vivo anti-tumor effects of A. membranaceus were investigated. Five bioactive fractions were isolated from the root of A. membranaceus, the fraction designated as AI was found to be the most potent among the five fractions with respect to its mitogenicity on murine splenocytes. Besides investigating the cytostatic effect of AI, its activities on macrophage function, tumor necrosis factor production, induction of lymphokine-activated killer cell and tumor cell differentiation were also examined. The macrophage-like tumors and the myeloid tumors were found to be more sensitive to the cytostatic activity of AI, whereas the fibroblast-like tumors and the mouse Ehrlich ascites tumor appeared to be relatively resistant. Moreover, AI could effectively suppress the in vivo growth of syngeneic tumor in mice. Results showed that murine macrophage pretreated with AI had increased in vitro and in vivo cytostatic activities towards MBL-2 tumor. AI could also act as a priming agent for tumor necrosis factor production in tumor-bearing mice. Preincubation of mouse splenocytes with AI could induce in vitro lymphokine-activated killer-like activity towards WEHI-164 cell. Furthermore, AI was able to induce monocytic differentiation of both human and murine cells in vitro. AI administered in vivo could even partially restore the depressed mitogenic response in tumor-bearing mice. Collectively, the results showed that A. membranaceus could exhibit both in vitro and in vivo anti-tumor effects, which might be achieved through activating the anti-tumor immune mechanism of the host.

Animals↗
PubMedDate not supplied

Hormonal therapy in early and advanced breast cancer.

While some of the most intriguing data on the development of hormonal therapy for breast cancer have come from studies on aromatase inhibitors (AIs), few trials have compared these agents directly, with the exception of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. Based on the latest results from this trial and on previous investigations of other AIs, a proposed sequence of hormonal therapies (including anastrozole, tamoxifen, letrozole, fulvestrant, and megestrol acetate) for the treatment of breast cancer is beginning to emerge for various patient populations.

Anastrozole↗
PubMed2006

Coronary heart disease and stroke with aromatase inhibitor, tamoxifen, and menopausal hormone therapy use.

Results from the Women's Health Initiative randomized clinical trials of hormone therapy provide the clinical context for interpreting tamoxifen and aromatase inhibitor (AI) findings regarding coronary heart disease (CHD) and stroke. Of note is the potential link between increased stroke risk and increased dementia risk seen with the use of estrogen alone and the combination of estrogen/progestin. Like hormone therapy, tamoxifen has been found to generally lower low-density lipoprotein and total cholesterol but increase triglyceride levels. The preponderance of clinical evidence suggests that tamoxifen increases stroke risk and has no effect or modestly reduces CHD risk. Aromatase inhibitors generally do not influence low-density lipoprotein cholesterol and could modestly increase high-density lipoprotein cholesterol and reduce triglyceride levels. Current but limited evidence suggests that AIs have a modest increase or no effect on CHD as a class or as individual agents compared with tamoxifen. The influence of AIs on stroke is unsettled, and within-class differences might exist. In the adjuvant breast cancer setting, based on available evidence, the influence of AIs on CHD or stroke will infrequently influence overall patient outcome. If remaining issues are to be addressed, more rigorous CHD and stroke assessment procedures are needed in future trials evaluating AIs.

Aged↗
PubMed2006

Arterial ischemic stroke and cerebral venous thrombosis in children: a 12-year Argentinean registry.

Over a 12-year period, 112 consecutive children with arterial ischemic stroke (AIS) and 38 children with cerebral venous thrombosis (CVT) were prospectively recruited at a single pediatric center in Argentina. One or more underlying clinical conditions were identified in most patients (55%) with AIS and in almost all patients with CVT. Inherited and/or acquired prothrombotic disorders were detected in 17% of the patients with AIS and in 34% of the children with CVT. No associations between factor V Leiden or prothrombin G20210A mutation and children with AIS or CVT were found. Antithrombotic agents (i.e., aspirin, low-molecular-weight heparin and acenocoumarol) were administered without major hemorrhagic complications. In our cohorts, mortality due to the thrombotic episode was 1.8% in children with AIS. No child with CVT died from his or her thrombotic episodes. Three children (3.2%) and 1 adolescent (1.1%) with AIS had thrombotic progression and recurrence, respectively. A large percentage of children with AIS (68%) and CVT (32%) have had some kind of sequels that caused serious disability in approximately half the cases.

Adolescent↗
PubMed2003

Development of aromatase inhibitors and their pharmacologic profile.

Major advances have been recently made in the treatment of postmenopausal women with hormone-sensitive breast cancer. It is widely accepted that estrogen is associated with the progression of hormone-sensitive breast cancer. Whereas previous therapy was based on surgical ablation (ovariectomy, adrenalectomy, and hypophysectomy) or additive treatment (estrogens, androgens), more recently antiestrogens (in premenopausal as well as postmenopausal women), medical ovarian ablation, and aromatase inhibition have replaced these procedures. The current focus of clinical research efforts is to maximize efficacy with these agents and determine an effective treatment strategy for these patients. This article reviews the development of aromatase inhibitors and inactivators (AIs), with particular emphasis on the potent third-generation agents now available. Also provided is information on the relative potency and efficiency of estrogen synthesis inhibition with these agents. Results from in vitro and in vivo studies of AIs suggest that there is variability in efficacy among agents in this class, and the potential clinical implications of these variations are discussed.

Antineoplastic Agents↗
PubMed2006

Clinicians' attitudes regarding barriers to the implementation of psychiatric advance directives.

OBJECTIVE: Psychiatric advance directives (PADs) may include documenting advance instructions (AIs) and/or designating health care agents (HCAs). Laws authorizing PADs have proliferated in the past decade, but there has been little research regarding perceptions of barriers to the implementation of PADs among groups of mental health professionals. METHODS: A total of N=591 mental health professionals (psychiatrists, psychologists, and social workers) completed a survey regarding their perceptions of potential barriers to the effective implementation of PADs. RESULTS: Across the three professional groups barriers related to operational features of the work environment (e.g., lack of communication between staff, lack of access to the document) were reported at a higher rate than clinical barriers (e.g., inappropriate treatment requests, consumers' desire to change their mind about treatment during crises). However, psychiatrists were more likely to report clinical barriers to implementation than both psychologists and social workers. In multivariable analyses, legal defensiveness, employment in public sector mental health services, and a belief that treatment refusals will outweigh the benefits of PADs were associated with more perceived barriers, whereas age and endorsing positive perceptions of PADs were associated with fewer perceived barriers. CONCLUSION: Psychiatrists, psychologists and social workers tend to perceive significant potential barriers to PADs, related to operational aspects of these professionals' work environment as well as certain clinical features of PADs for persons with severe mental illness. Additionally, legal defensiveness and general endorsement of PADs appear to shape perceptions of barriers to the effective implementation of PADs.

Adult↗