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Biomedical subjects

Douglas Yee

Publications and source records attributed to Douglas Yee.

At least 19 recordsLinked to original sources
PubMed2007

Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin.

The type I insulin-like growth factor receptor (IGF1R) and insulin receptor (IR) are structurally and functionally related heterotetrameric receptors. Activation of IGF1R has been shown to regulate breast cancer cell biology, and it has become an attractive therapeutic target. Most strategies have focused on targeting IGF1R alone without affecting IR levels given the known physiologic functions of IR. Human breast cancer cell lines and tissues revealed mRNA expression of both IGF1R and IR. Because alphabeta chains of IGF1R and IR form hybrid receptors, we hypothesized that agents solely targeting IGF1R may affect tumor biology mediated by IGF1R/IR hybrids and IR. We used small interfering RNA (siRNA) technology to specifically down-regulate IGF1R by 60% to 80% in the MDA-435/LCC6 cell line, which was sufficient to diminish activation of IGF1R by IGF-I. IGF1R down-regulation by siRNA did not affect IR levels but, interestingly, sensitized cells to insulin activation of downstream signaling pathways in several breast cancer cell lines. IGF1R siRNA treatment diminished hybrid receptor formation, suggesting that specific down-regulation of IGF1R resulted in enhanced holo-IR formation. In addition, IGF1R down-regulation increased insulin binding consistent with the formation of an increased number of holo-IR on the cell surface. Accordingly, insulin-stimulated glucose uptake was enhanced on IGF1R down-regulation. In conclusion, our data suggest that specific siRNA targeting of IGF1R alone in breast cancer increases insulin sensitivity. Because IR also activates signaling pathways similar to IGF1R in breast cancer cells, agents targeting both receptors may be necessary to disrupt the malignant phenotype regulated by this growth factor system.

Breast Neoplasms↗
PubMed2006

Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice.

Although antiandrogen therapy has been shown effective in treating prostatic tumors, it is relatively ineffective in treating benign prostatic hyperplasia (BPH). In an attempt to understand better the role of androgens in the development of the normal prostate and BPH, we studied the relative effects of testosterone and IGF-I on the development of the two compartments of the prostate in castrated IGF-I((-/-)) male mice. Here we report that IGF-I stimulated the development of the fibromuscular compartment, but testosterone inhibited it (stromal epithelial ratio 2.17 vs. 0.83, respectively; P < 0.001). Testosterone also impaired IGF-I induced insulin receptor substrate-1 phosphorylation and cell division, and increased apoptosis in fibromuscular tissue. In sharp contrast IGF-I and testosterone both stimulated the development of the glandular compartment individually and together. The combined effects were either additive or synergistic on compartment size, cell division, insulin receptor substrate-1 phosphorylation, and probasin production. Together they also had a greater inhibitory effect on apoptosis in gland tissue. To determine whether IGF-I inhibition would inhibit both fibromuscular and glandular compartments, we tested the effect of IGF binding protein-1 on prostate development in two different models: castrated Ames dwarf mice and eugonadal normal male mice. IGF binding protein-1 blocked bovine GH-induced fibromuscular and glandular development in both. It also inhibited epithelial cell division and increased apoptosis in both prostate compartments in the eugonadal mice. The observed discordance between IGF-I and testosterone control of prostate compartment development might explain the relative failure of 5alpha-reductase inhibition in BPH and why testosterone inhibition might theoretically reduce gland volume but increase fibromuscular tissue. The work also provides a rationale for considering IGF-I inhibition as therapy for BPH to reduce the size of both prostate compartments.

Androgen-Binding Protein↗
PubMed2006

Randomized controlled trial of weight training and lymphedema in breast cancer survivors.

PURPOSE: Lymphedema is a common condition that breast cancer survivors face. Despite a lack of supporting evidence from prospective observational studies, occupational and leisure time physical activity are feared to be possible risk factors for lymphedema onset or exacerbation. We examined effects of supervised upper- and lower-body weight training on the incidence and symptoms of lymphedema in 45 breast cancer survivors who participated in the Weight Training for Breast Cancer Survivors study. METHODS: Participants were on average 52 years old, 4 to 36 months post-treatment, and had axillary dissection as part of their treatment. Thirteen women had prevalent lymphedema at baseline. The intervention was twice-a-week weight training over a period of 6 months. Lymphedema was monitored at baseline and 6 months by measuring the circumference of each arm, and by self-report of symptoms and clinical diagnosis. RESULTS: None of the intervention-group participants experienced a change in arm circumferences > or = 2.0 cm after a 6-month exercise intervention. Self-reported incidence of a clinical diagnosis of lymphedema or symptom changes over 6 months did not vary by intervention status (P = .40 and P = .22, respectively). CONCLUSION: This is the largest randomized controlled trial to examine associations between exercise and lymphedema in breast cancer survivors. The results of this study support the hypotheses that a 6-month intervention of resistance exercise did not increase the risk for or exacerbate symptoms of lymphedema. These results herald the need to start reevaluating common clinical guidelines that breast cancer survivors avoid upper body resistance activity for fear of increasing risk of lymphedema.

Breast Neoplasms↗
PubMed2006

Effects of weight training on quality of life in recent breast cancer survivors: the Weight Training for Breast Cancer Survivors (WTBS) study.

BACKGROUND: Aerobic exercise training has been shown to have beneficial effects on quality of life (QOL) in breast cancer survivors. However, the effects of weight training on psychological benefits are unknown. We sought to examine the effects of weight training on changes in QOL and depressive symptoms in recent breast cancer survivors. METHODS: A convenience sample of 86 survivors (4-36 months posttreatment) was randomized into treatment and control groups. The primary outcomes were changes in QOL (CARES short form) and depressive symptoms (CES-D) between baseline and month 6 in this randomized controlled trial. RESULTS: Over 6 months the physical global QOL score improved in the treatment group compared with the control group (Standardized Difference = 0.62, P = .006). The psychosocial global score also improved significantly in the treatment group compared with the control group (Standardized Difference = 0.52, P = .02). There were no changes in CES-D scores. Increases in upper body strength were correlated with improvements in physical global score (r = 0.32; P <.01) and psychosocial global score (r = 0.30; P <.01). Increases in lean mass were also correlated with improvements in physical global score (r = 0.23; P <.05) and psychosocial global score (r = 0.24; P <.05). CONCLUSION: Twice-weekly weight training for recent breast cancer survivors may result in improved QOL, in part via changes in body composition and strength.

Adult↗
PubMed2006

Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: implications for anti-insulin-like growth factor therapy in breast cancer.

Insulin-like growth factor-I (IGF-I), IGF-II, and insulin have all been implicated in regulating several aspects of the malignant phenotype via the type I IGF receptor (IGF1R) and insulin receptor (IR). We have previously shown that a chimeric single-chain antibody against IGF1R (scFv-Fc) and a murine antibody EM164 down-regulate IGF1R, making breast cancer cells unresponsive to IGF-I. To determine if IR signaling is affected, we examined regulation of IR in MCF-7 cells after exposure to these antibodies. Surprisingly, both scFv-Fc and EM164 resulted in decreased levels of IR in vitro and in vivo despite their lack of reactivity against IR. Twenty-four-hour pretreatment with EM164 also inhibited insulin-mediated phosphorylation of IR and insulin-stimulated proliferation of MCF-7 cells. Neither scFv-Fc nor EM164 caused down-regulation of IR in cells that express very low levels of IGF1R or no IGF1R. Expression of IGF1R was required for IR down-regulation, which was specific as neither antibody caused down-regulation of beta1 integrin or epidermal growth factor receptor. Reagents that disrupt lipid rafts inhibited IR down-regulation by the antibodies, suggesting that IR in close physical proximity to IGF1R in lipid rafts was being endocytosed. Our data show that down-regulation of IR by monoclonal antibodies against IGF1R requires the coexpression of IGF1R and may be due to endocytosis of hybrid IR/IGF1R or holo-IR. Thus, antibodies against IGF1R provide inhibition of both IGF and insulin signaling in cancer cells.

Animals↗
PubMed2006

Characterization of an in vitro cell culture bioreactor system to evaluate anti-neoplastic drug regimens.

A dynamic 3-dimensional tissue culture system has been developed that will allow for control of gemcitabine exposure to mimic concentration-time profiles measured from biologic samples. Gemcitabine was infused into a central reservoir. Media is mixed and delivered through hollow fiber capillaries, where it diffuses into the extracapillary space containing anchorage-dependent MDA-231 cells. To test for control of gemcitabine concentration-time profiles, drug was first infused through bioreactors without cells, and gemcitabine concentrations were measured with HPLC. Concentrations could be controlled to simulate 30-min and 2.5 h infusions, and were similar in both the lumen and extracapillary space. MDA-231 cells were then seeded into control (n = 4) and gemcitabine treatment (n = 4) groups, and maintained in culture for 2 weeks. Gemcitabine (5.3 mg) was infused over 30 min to the treatment group, and blank media to the control group. Accuracy of measured gemcitabine maximum concentration (Cmax) was 83.4%, and area under the curve (AUC), 106.2%, relative to pre-experimental theoretical values. With cells present, gemcitabine AUC in the extracapillary space was 32% of the value in the lumen. For the control group, 21.2 million cells (94.3% viable) were recovered, and for the gemcitabine-treated group, 16.8 million cells (87.1 % viable). Flow cytometry showed that 13.3 % of cells in the control group were in S-phase and 34.3 % in the gemcitabine-treated group were in S-phase (p = 0.003). In conclusion, gemcitabine concentration-time profiles could be accurately controlled through dosage, infusion rate, and pump flow rate, and cells could be recovered afterward to evaluate drug treatment.

Antimetabolites, Antineoplastic↗
PubMed2006

Inhibitors of insulin-like growth factor signaling: a therapeutic approach for breast cancer.

The peptide growth factors IGF-I and IGF-II not only play a role in the development of the mammary gland but are also implicated in breast cancer. Several reagents disrupting IGF signaling have been developed and clinical trials validating IGF signaling as a target in cancer therapy are underway. This review highlights the approaches to inhibiting IGF signaling in breast cancer.

Antibodies, Neoplasm↗
PubMed2006

Effects of insulin-like growth factor-1 receptor inhibition in mesothelioma. Thoracic Surgery Directors Association Resident Research Award.

BACKGROUND: Malignant mesothelioma is a devastating disease with a poor prognosis. Recent data have shown that insulin-like growth factor-1 receptor (IGF-1R) may play a role in oncogenic signaling. Our aim was to evaluate the effect of a novel IGF-1R inhibitor, NVP-AEW541, on cell growth and IGF associated pathways. METHODS: Malignant mesothelioma cell lines, H2373 and H2461, previously shown to activate the IGF pathway were grown in culture. The adherent cells, initially plated at 5 x 10(5) cells/plate, were treated for 72 hours, in triplicate, with varying concentration of NVP-AEW541 (0, 1, 5, 10, 20, and 50 microM). Viable cells were counted every 24 hours. Additionally, separate cultures in serum-free medium were treated with NVP-AEW541, then stimulated with IGF and lysates collected for immunoblot analysis. RESULTS: In both cell lines, 0, 1, 5, and 10 microM showed an inhibitory or static effect, while 20 and 50 microM were cidal. Immunoblot analysis demonstrated that phosphorylation of IGF-1R was inhibited by NVP-AEW541 at higher concentration. Phosphorylation of mitogen-activated protein kinase and Akt, downstream IGF pathway mediators, were also shown to be repressed by drug treatment. CONCLUSIONS: NVP-AEW541 has a concentration-dependent inhibitory effect on mesothelioma cells in culture. NVP-AEW541 acts by inhibition of IGF-1R phosphorylation. Inhibition effects phosphorylation of downstream mediators in a dose-dependent fashion. Inhibition of the IGF pathway decreases viability of mesothelioma cell culture. Further evaluation of NVP-AEW541, and other selective IGF-1R inhibitors, may play an important role in multimodal treatment of malignant mesothelioma.

Antineoplastic Agents↗
PubMed2006

Naloxone acts as an antagonist of estrogen receptor activity in MCF-7 cells.

Estrogen promotes the growth of breast cancer via estrogen receptors (ER). Earlier studies showed that the opioid receptor antagonist naloxone inhibits MCF-7 breast cancer growth in mice. We examined the cellular and molecular mechanism of naloxone antagonism of ERalpha activity in human MCF-7 cells. Naloxone (100 nmol/L) inhibited 17beta-estradiol (E2)-induced (10 nmol/L) MCF-7 cell proliferation by 65% and mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation. Naloxone blocked the E2-induced activation of ERalpha, with 85% inhibition after 5 minutes and 100% recovery after 60 minutes. This assay is based on quantitation of E2-activated nuclear ERalpha binding to the immobilized coactivator peptide. A significant decrease in E2-induced ERalpha transactivation was observed in the presence of naloxone in the estrogen response element-luciferase reporter assay (P < 0.05, E2 versus E2 + naloxone). Naloxone also blocked E2-induced down-regulation of ERalpha mRNA at 30 minutes and 6 hours. Although naloxone inhibits ERalpha activity directly, it also induces a cross-talk between mu-opioid receptor (MOR) and ERalpha. Immunoprecipitates with anti-MOR antibody showed the presence of ERalpha in cells incubated with E2 in the presence of naloxone but not in cells incubated with E2 or naloxone alone. Higher amounts of ERalpha associated with MOR after 60 minutes compared with 10 minutes of incubation. Naloxone inhibited E2-bovine serum albumin-FITC binding to plasma membrane-associated ERalpha and also inhibited the direct binding of [3H]E2 to ERalpha. Thus, naloxone modulates ERalpha activity directly as well as indirectly via MOR. This study suggests that naloxone-like compounds can be developed as novel therapeutic molecules for breast cancer therapy.

Animals↗
PubMed2006

Targeting the insulin-like growth factor axis as a cancer therapy.

The insulin-like growth factor (IGF) axis has been implicated in malignant transformation and in tumor cell biology. Human population studies have demonstrated that high levels of circulating IGF-I are associated with an increased risk of certain malignancies. Many model systems show that IGFs stimulate tumor cell proliferation, survival and metastasis. In a new era of anticancer treatments aimed at tumor-specific targets, efforts are in progress for the development of novel anti-IGF therapies. Disrupting type I IGF-receptor (IGF-IR) function in vitro and in vivo results in tumor growth inhibition in several model systems. Antireceptor therapies in particular have provided encouraging results leading to the approval of the first Phase I human clinical trial targeting IGF-IR. Additional methods to decrease levels of circulating IGF-I and II have also been developed. In principle, a benefit of targeted therapies could be their relative lack of toxicity compared with conventional chemotherapy. Anti-IGF-IR therapies, however, raise theoretical concerns for the development of serious side effects, including diabetes. As targeted therapies against the IGF axis continue to be developed, efforts will need to be made to minimize the side effects that result from blocking normal ligand and receptor-induced functions.

Down-Regulation↗
PubMed2005

Type I insulin-like growth factor receptor as a therapeutic target in cancer.

Data from experimental model systems and population studies have implicated type I insulin-like growth factor receptor (IGF1R) signaling in many different human cancers. Drugs to disrupt IGF1R function have been developed and are now entering clinical trial. This brief review will identify key areas to consider as these clinical trials move forward.

Animals↗
PubMed2005

Imaging in breast cancer: Magnetic resonance spectroscopy.

A technique called in vivo magnetic resonance spectroscopy (MRS) can be performed along with magnetic resonance imaging (MRI) to obtain information about the chemical content of breast lesions. This information can be used for several clinical applications, such as monitoring the response to cancer therapies and improving the accuracy of lesion diagnosis. Initial MRS studies of breast cancer show promising results, and a growing number of research groups are incorporating the technique into their breast MRI protocols. This article introduces 1H-MRS of the breast, reviews the literature, discusses current methods and technical issues, and describes applications for treatment monitoring and lesion diagnosis.

Breast Neoplasms↗
PubMed2005

Insulin-like growth factor-I and breast cancer therapy.

Targeting hormonal and growth factor signaling pathways has proven to be useful in the treatment of breast cancer. In vitro, animal, and epidemiologic evidence provide a rationale for the relevance of the insulin-like growth factor (IGF) system to breast cancer biology. The IGF system has been implicated in promoting mitogenic, metastatic, and antiapoptotic phenotypes in breast cancer. As a consequence of the ability of IGF to promote tumorigenesis, pharmacologic interventions targeting the IGF system are being devised. Such strategies include decreasing ligand production, ligand binding, or receptor activation. In this article, directed anti-IGF strategies and the possible clinical impact of using such therapies for treating breast cancer are discussed.

Antineoplastic Agents↗
PubMed2005

Multiple signaling pathways are activated during insulin-like growth factor-I (IGF-I) stimulated breast cancer cell migration.

In order to display the full metastatic phenotype, the cancer cell must acquire the ability to migrate. In breast cancer, we have previously shown that insulin-like growth factor I (IGF-I) enhances cell motility in the highly metastatic MDA-231BO cell line by activating the type I IGF receptor (IGF1R). This motility response requires activation of IRS-2 and integrin ligation. In order to identify the key molecules downstream of IRS-2, we examined several signaling pathways known to be involved in cell motility. Focal adhesion kinase (FAK) was not activated by IGF-I, but IGF-I caused redistribution of FAK away from focal adhesion plaques. IGF-I treatment of MDA-231BO cells activated RhoA and inhibition of Rho-kinase (ROCK) inhibited the IGF-mediated motility response. The mitogen activated protein kinase (MAPK), p38, was also activated by IGF-I and inhibition of p38 by SB203580 blocked IGF-I induced cell motility. ROCK inhibition with Y-27632 also inhibited p38 phosphorylation suggesting that p38 lies downstream of ROCK. Both Erk1,2 and phosphatidyl-3 kinase (PI3K) were required for IGF-I stimulated cell motility, but only PI3K appeared to be directly downstream of IGF-I. Thus, IGF-I activation of its receptor coordinates multiple signaling pathways required for cell motility. Defining the key molecules downstream of the type I IGF receptor may provide a basis for optimizing therapies directed at this target.

Amides↗
PubMed2005

Memory enhancement by a semantically unrelated emotional arousal source induced after learning.

It has been well established that moderate physiological or emotional arousal modulates memory. However, there is some controversy about whether the source of arousal must be semantically related to the information to be remembered. To test this idea, 35 healthy young adult participants learned a list of common nouns and afterward viewed a semantically unrelated, neutral or emotionally arousing videotape. The tape was shown after learning to prevent arousal effects on encoding or attention, instead influencing memory consolidation. Heart rate increase was significantly greater in the arousal group, and negative affect was significantly less reported in the non-arousal group after the video. The arousal group remembered significantly more words than the non-arousal group at both 30 min and 24 h delays, despite comparable group memory performance prior to the arousal manipulation. These results demonstrate that emotional arousal, even from an unrelated source, is capable of modulating memory consolidation. Potential reasons for contradictory findings in some previous studies, such as the timing of "delayed" memory tests, are discussed.

Adult↗
PubMed2005

Adding in vivo quantitative 1H MR spectroscopy to improve diagnostic accuracy of breast MR imaging: preliminary results of observer performance study at 4.0 T.

PURPOSE: To determine whether the addition of in vivo quantitative hydrogen 1 (1H) magnetic resonance (MR) spectroscopy can improve the radiologist's diagnostic accuracy in interpreting breast MR images to distinguish benign from malignant lesions. MATERIALS AND METHODS: The study was approved by the institutional review board and, where appropriate, was compliant with the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Fifty-five breast MR imaging cases-one lesion each in 55 patients aged 24-66 years with biopsy-confirmed findings-were retrospectively evaluated by four radiologists. Patients were examined with contrast material-enhanced fat-suppressed T1-weighted 4.0-T MR imaging. The concentration of total choline-containing compounds (tCho) was quantified by using single-voxel 1H MR spectroscopy. For each case, the radiologists were asked to give the percentage probability of malignancy, the Breast Imaging and Reporting Data System category, and a recommendation for patient treatment. Two interpretations were performed for each case: The initial interpretation was based on the lesion's morphologic features and time-signal intensity curve, and the second interpretation was based on the lesion's morphologic features, time-signal intensity curve, and tCho concentration. Receiver operating characteristic (ROC), Wilcoxon signed rank, kappa statistic, and accuracy (based on the area under the ROC curve) analyses were performed. RESULTS: Of the 55 lesions evaluated, 35 were invasive carcinomas and 20 were benign. The addition of 1H MR spectroscopy resulted in higher sensitivity, specificity, accuracy, and interobserver agreement for all four radiologists. More specifically, two of the four radiologists achieved a significant improvement in sensitivity (P=.03, P=.03), and all four radiologists achieved a significant improvement in accuracy (P = .01, P = .05, P = .009, P < .001). CONCLUSION: Current study results suggest that the addition of quantitative 1H MR spectroscopy to the breast MR imaging examination may help to improve the radiologist's ability to distinguish benign from malignant breast lesions.

Adolescent↗