PubMed Health⌕ Search

Biomedical subjects

M Pollak

Publications and source records attributed to M Pollak.

At least 37 records · Page 2Linked to original sources
PubMed2000

Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group.

PURPOSE: The efficacy and tolerability of anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) and tamoxifen were compared as first-line therapy for advanced breast cancer in 353 postmenopausal women. PATIENTS AND METHODS: The randomized, double-blind, multicenter study was designed to evaluate anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with hormone receptor-positive tumors or tumors of unknown receptor status who were eligible for endocrine therapy. Primary end points were objective response (OR), defined as complete (CR) or partial (PR) response, time to progression (TTP), and tolerability. RESULTS: Anastrozole was as effective as tamoxifen in terms of OR (21% v 17% of patients, respectively), with clinical benefit (CR + PR + stabilization > or = 24 weeks) observed in 59% of patients on anastrozole and 46% on tamoxifen (two-sided P =.0098, retrospective analysis). Anastrozole had a significant advantage over tamoxifen in terms of TTP (median TTP of 11.1 and 5.6 months for anastrozole and tamoxifen, respectively; two-sided P =.005). The tamoxifen:anastrozole hazards ratio was 1.44 (lower one-sided 95% confidence limit, 1.16). Both treatments were well tolerated. However, thromboembolic events and vaginal bleeding were reported in fewer patients who received anastrozole compared with those who received tamoxifen (4.1% v 8.2% [thromboembolic events] and 1.2% v 3.8% [vaginal bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Furthermore, we observed both a significant increase in TTP and a lower incidence of thromboembolic events and vaginal bleeding with anastrozole. These findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with advanced breast cancer.

Adult↗
PubMed2000

Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells.

Silibinin, a naturally occurring flavonoid antioxidant found in the milk thistle, has recently been shown to have potent antiproliferative effects against various malignant cell lines, but the underlying mechanism of action remains to be elucidated. We investigated the effect of silibinin on androgen-independent prostate cancer PC-3 cells. At pharmacologically achievable silibinin concentrations (0.02-20 microM), we observed increased insulin-like growth factor-binding protein 3 (IGFBP-3) accumulation in PC-3 cell conditioned medium and a dose-dependent increase of IGFBP-3 mRNA abundance with a 9-fold increase over baseline at 20 microM silibinin. An IGFBP-3 antisense oligodeoxynucleotide that attenuated silibinin-induced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin. We also observed that silibinin reduced insulin receptor substrate 1 tyrosine phosphorylation, indicating an inhibitory effect on the insulin-like growth factor I receptor-mediated signaling pathway. These results suggest a novel mechanism by which silibinin acts as an antiproliferative agent and justify further work to investigate potential use of this compound or its derivatives in prostate cancer treatment and prevention.

Androgens↗
PubMed2000

Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density.

Insulin-like growth factors (IGFs) and insulin-like growth factor-binding proteins (IGFBPs) play a role in the normal development of breast tissue and possibly in the etiology of breast cancer. Breast density is one of the strongest predictors of breast cancer. In a cross-sectional analysis within the Nurses' Health Study, we compared the associations of plasma levels of endogenous IGF-I and IGFBP-3 with breast density in 65 premenopausal and 192 postmenopausal women. The digitized film screen mammograms were evaluated by the computer-assisted Toronto method, in which visually selected gray-scale cut points are used to assess breast density. Generalized linear models and Spearman's partial correlation coefficients described the associations between breast density and IGF-I, IGFBP-3, and the IGF-I:IGFBP-3 ratio. Premenopausal breast density was positively correlated with IGF-I and inversely correlated with IGFBP-3; the association was strongest for the IGF-I:IGFBP-3 ratio and breast density (r = 0.39; P = 0.004). In contrast, the correlation between breast density and the IGF-I:IGFBP-3 ratio among postmenopausal women was -0.02 (P = 0.83). The associations of IGF-I:IGFBP-3 ratio with breast density differed significantly between premenopausal and postmenopausal women (P = 0.01). Mammographic density is positively associated with plasma IGF-I levels and inversely associated with plasma IGFBP-3 levels among premenopausal women, but not among postmenopausal women. These results are consistent with previous studies that showed a positive association between a higher IGF-I:IGFBP-3 ratio and subsequent risk of breast cancer only among premenopausal women. The findings raise the possibility that premenopausal levels of IGF-I and IGFBP-3 could be in the etiological pathway that relates higher breast density with increased breast cancer risk.

Aged↗
PubMed2000

Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models.

Although insulin-like growth factor binding protein-5 (IGFBP-5) has been shown to be implicated in prostate cancer progression, the functional role of IGFBP-5 in progression to androgen-independence remains largely undefined. Here, we demonstrate substantial up-regulation of IGFBP-5 during castration-induced regression and androgen-independent (AI) progression in the mouse androgen-dependent (AD) Shionogi tumor model. To analyze the functional significance of these changes in IGFBP-5, human AD LNCaP prostate cancer cells were stably transfected with IGFBP-5 gene, and IGFBP-5-overexpressing LNCaP tumors progressed significantly faster to androgen independence after castration compared with controls. Antisense mouse IGFBP-5 oligodeoxynucleotides (ODNs) were then designed that reduced IGFBP-5 expression in Shionogi tumor cells in vitro in a dose-dependent and sequence-specific manner. Growth of Shionogi tumor cells was inhibited by antisense IGFBP-5 ODN treatment in a time- and dose-dependent manner, which could be reversed by exogenous IGF-I. However, antisense IGFBP-5 ODN treatment had no additive inhibitory effect on Shionogi tumor cell growth when IGF-I activity was neutralized by anti-IGF-I antibody. Antisense IGFBP-5 ODN treatment resulted in decreased mitogen-activated protein kinase activity and number of cells in the S + G2-M phases of the cell cycle that directly correlated with reduced proliferation rate of Shionogi tumor cells. Systemic administration of antisense IGFBP-5 ODN in mice bearing Shionogi tumors after castration significantly delayed time to progression to androgen independence and inhibited growth of AI recurrent tumors. These findings suggest that up-regulation of IGFBP-5 after castration serves to enhance IGF bioactivity and raise the possibility that the response of prostate cancer to androgen withdrawal can be enhanced by strategies, such as antisense IGFBP-5 ODN therapy, that target IGF signal transduction.

Androgens↗
PubMed2000

Aging effects in an anderson insulator

Aging, commonly observed in glasses, is a manifestation of breakdown of time-translational invariance. Here we demonstrate experimentally aging effects in the electronic system of an Anderson insulator. The aging phenomenon in the electron glass appears to be much less sensitive to temperature than in other systems. The differences in the behavior of the electron glass and a spin glass system are discussed in terms of some microscopic differences between the two systems.

Journal Article↗
PubMed2000

[Neonatal hyperparathyroidism secondary to unknown maternal hypoparathyroidism].

UNLABELLED: Vitamin D or its analogue (calcitriol) is an effective treatment for hypoparathyroidism during pregnancy. Normal babies are delivered and very few cases of associated neonatal hyperparathyroidism are reported. CASE REPORT: We report the case of a baby born to a mother suffering unknown hypoparathyroidism. He was delivered prematurely by cesarean section for birth asphyxia. His mother had had recurrent bouts of impetigo herpetiformis for several months. Severe demineralization associated with decreased plasma calcium level were observed at birth. The PTH level was very high (955 ng/mL) in the baby and very low in the mother, leading to the diagnosis. The baby was given intravenous calcium gluconate, oral 1 alpha-hydroxyvitamin D and mechanical ventilation. Normal plasma calcium level was reached on day 2. PTH level improved by one month of age. Because of impaired respiratory mechanics and bronchopulmonary dysplasia, the baby was kept on ventilation for 58 days. By 20 months of age, he was in good health despite a small height for his age. CONCLUSION: In such cases 1 alpha-hydroxyvitamin D seems to be very effective but plasma and urinary calcium levels need careful monitoring.

Adult↗
PubMed2000

Insulin-like growth factor physiology and cancer risk.

In the past few years, both laboratory investigations and population studies have provided strong circumstantial evidence that insulin-like growth factor (IGF) physiology influences cancer risk. In contrast to the influence of germ line mutations that are rare but are associated with very high risks, the impact of inter-individual variability in IGF physiology on risk appears to be modest but to effect a relatively high percentage of the population. Although this field of investigation is young, attention is already being given to the possibility that it may be relevant to clinical assessment of risk and/or to the identification of novel prevention strategies and intermediate endpoints. This review summarises key results in this field and provides a hypothesis concerning the mechanism by which IGF physiology influences risk of common epithelial cancers including those of breast, prostate, lung and colon.

Breast Neoplasms↗
PubMed2000

The question of a link between insulin-like growth factor physiology and neoplasia.

The results of both population and laboratory studies suggest that the physiology of insulin-like growth factors (IGFs) has important influences on cancer biology and cancer risk. This review highlights recent laboratory and epidemiological results in this rapidly evolving area of investigation. There is no direct evidence to suggest that growth hormone (GH) treatment of GH-deficient patients increases their risk of neoplasia, but recent research reinforces the need for careful surveillance. The monitoring of serum IGF-I levels may be advisable to help avoid inadvertent over-treatment, particularly in individuals undergoing long-term GH replacement therapy.

Growth Hormone↗
PubMed2000

H19 sense and antisense transgenes modify insulin-like growth factor-II mRNA levels.

The oppositely-imprinted genes insulin-like growth factor-II (IGF2) and H19, a putative tumor suppressor, often show coordinate, reciprocal regulation and are believed to play a role in carcinogenesis. To explore the possible interactions between these genes, we stably transfected diHepG2 cells with a plasmid containing either the sense or the antisense H19 cDNA sequences and verified their expression by Northern analysis and by RNase protection analysis. Levels of H19, IGF2 and gamma-actin mRNA were quantified by competitive RT-PCR analysis. Although H19 sense transgene overexpression (n = 24 clones) did not decrease the low, basal levels of IGF2 mRNA compared to control cells, levels of IGF2 mRNA were positively correlated with the levels of H19 antisense mRNA (P < 0.0001, n = 40 clones). Furthermore, the increase in IGF2 mRNA level was accompanied by an elevation of IGF-II peptide in conditioned media. To see if H19 mRNA had a specific effect on transcription, we also performed transient transfections with reporter gene constructs containing IGF2 promoter 3 in the presence of sense or antisense H19 cDNA sequences under control of a cytomegalovirus promoter. We show a lower reporter gene activity from reporter gene constructs in the presence of sense H19 cDNA than from those with antisense or neomycin. Our results suggest that H19 participates in the repression of IGF2, at least in part through effects on IGF2 transcription, an effect which may contribute to its action as a tumor suppressor.

Actins↗
PubMed2000

Modulation of transforming growth factor beta1 gene expression in the mammary gland by insulin-like growth factor I and octreotide.

Transforming growth factor beta1 (TGF-beta1) has been shown to exhibit anti-proliferative activity for mammary gland epithelial cells and for human breast cancer cells. Insulin-like growth factor I (IGF-I), in contrast, is a well-characterized mitogenic and anti-apoptotic factor involved in mammary gland physiology. In order to examine the hypothesis that IGF-I suppresses TGF-beta1 expression in the mammary gland, we studied the effect of various manipulations of the growth hormone - IGF-I axis on TGF-beta1 mRNA abundance. Administration of IGF-I to intact animal suppressed TGF-beta1 mRNA levels in a dose-dependent manner to approximately 20% of control levels. Administration of the somatostatin analogue octreotide in a manner previously shown to acutely suppress the growth hormone - IGF-I axis increased mammary gland TGF-beta1 expression approximately 3-fold. Transgenic mice overexpressing growth hormone expressed TGF-beta1 in the mammary gland at only approximately 12% of the level of control animals, while mice IGF-I deficient due to the mutation expressed TGF-beta1 at slightly higher levels than control animals. The large differences in TGF-beta1 expression between control and GH-transgenic animals were correlated with major differences in architecture of the mammary gland, while the appearance of mammary glands of normal and animals was similar. These data document a previously unrecognized relationship between TGF-beta1 and IGF-I physiology in the mammary gland, and suggest a novel mechanism by which somatostatin analogues influence the proliferative behaviour of breast epithelial cells.

Animals↗
PubMed1999

Castration-induced apoptosis of androgen-dependent shionogi carcinoma is associated with increased expression of genes encoding insulin-like growth factor-binding proteins.

Insulin-like growth factor (IGF)-I has well-characterized mitogenic and antiapoptotic effects that are essential for maintenance of the normal prostate and may be important during regression of the normal prostate and/or prostate tumors induced by androgen-targeting therapies for prostate cancer. IGF-I activity is modulated by IGF-binding proteins (IGFBPs). Here we examine IGFBP expression during regression of androgen-dependent Shionogi carcinoma tumors after castration. In this model, we observe a 90% reduction in Shionogi tumors by 10 days postcastration. Northern blotting of RNA from tumors collected at various times after castration indicates a rapid induction of IGFBP-5 concomitant with apoptotic regression of tumors, as detected by Apoptag staining of tumor sections after castration. IGFBP-5 mRNA was not detectable in tumors from control animals, but levels increased 120-fold in tumors 3 days after castration. The mRNAs for IGFBP-3 and 4 were abundant in Shionogi tumors from intact mice and decreased to -33% and -20% of control, respectively. Castration had no significant effect on IGFBP-2 expression. Treatment with calcium channel blockers inhibited castration-induced apoptosis and tumor regression and also significantly inhibited up-regulation of IGFBP-5 after castration. These data provide strong evidence for a functional role of IGFBP-5 expression in mediating the apoptosis induced by androgen deprivation in androgen-dependent neoplasia.

Amlodipine↗
PubMed1999

Bicalutamide (Casodex)-induced prostate regression involves increased expression of genes encoding insulin-like growth factor binding proteins.

OBJECTIVES: To examine the effects of bicalutamide (Casodex), a pure antiandrogen with high specificity for the androgen receptor, on insulin-like growth factor binding protein (IGFBP) expression and apoptotic regression of the rat ventral prostate. METHODS: Rats were treated daily with 10 mg/kg body weight bicalutamide or vehicle alone. Ventral prostates were collected at various days of treatment. Northern blot analysis was performed to quantitate expression of genes encoding IGFBPs, and the TUNEL method was used to determine the extent of apoptosis in ventral prostate. RESULTS: In rats treated daily with bicalutamide, increases in mRNA levels of IGFBP-2, -3, -4, and -5 were detectable by Northern blotting by 6 hours and reached 6 to 10-fold of control levels after 5 days of treatment. The time-course of induction of apoptosis in the ventral prostate by bicalutamide, as detected in situ by the TUNEL method, corresponded to the time-course of induction of IGFBP expression. CONCLUSIONS: We demonstrate that apoptotic regression of the ventral prostate during bicalutamide treatment is accompanied by increased expression of IGFBP-2, -3, -4, and -5. Rapid induction of IGFBPs, which can limit access of insulin-like growth factors (IGFs) to the IGF-I receptor, may play a role in the induction of apoptosis by antiandrogens, particularly in view of the increasing evidence that IGF-I inhibits apoptosis. These results document a previously unrecognized effect of antiandrogens and extend our previous studies relating IGF physiology to prostate biology. Together with evidence that a strong positive correlation exists between plasma IGF-I levels and prostate cancer risk, our data suggest that IGF physiology may play a key role in prostate cancer biology and is strongly influenced by androgen-targeting therapies.

Androgen Antagonists↗