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M Pollak

Publications and source records attributed to M Pollak.

At least 91 records · Page 5Linked to original sources
PubMed1995

Low dose octreotide and tamoxifen in the treatment of adenocarcinoma of the pancreas.

BACKGROUND: Data from experimental studies suggest that a combination of octreotide, the long acting somatostatin analogue, octreotide, and tamoxifen improves the survival of animals with pancreatic cancer. METHODS: Twelve patients with a tissue diagnosis of ductal adenocarcinoma of the pancreas were treated with 100 micrograms of octreotide three times per day and tamoxifen 10 mg twice daily. The survival of the octreotide-tamoxifen group was compared with a historic cohort of 68 untreated patients with pancreatic cancer, matched for age, sex, and TNM stage. RESULTS: The median survival times for the octreotide-tamoxifen-treated group compared with the historic cohort were 12 and 3, months respectively. Actuarial one-year survival rates for the octreotide-tamoxifen-treated group compared with the historic cohort were 59% and 16%, respectively. CONCLUSIONS: In this study, patients with unresectable and resected ductal adenocarcinoma of the pancreas had an apparently increased survival when treated with a combination of octreotide and tamoxifen. A randomized controlled trial to examine this potential therapeutic benefit is now indicated.

Actuarial Analysis↗
PubMed1995

Insulin-like growth factor 1 (IGF-1) receptors, IGF-1, and IGF-2 are expressed in primary human sarcomas.

A variety of bone and soft-tissue sarcoma cell lines have been shown to express receptors for insulin-like growth factor-1 (IGF-1) and to respond mitogenically to IGF-1 in vitro. We have recently demonstrated evidence of IGF dependency in murine MGH-OGS and RIF-1 sarcomas, which express relatively high and intermediate levels of IGF-1 receptors. Overexpression of IGF-1 receptors and/or IGF ligands might, therefore, be a mechanism by which human bone and soft-tissue sarcomas obtain a proliferative advantage over normal adjacent tissues. Therefore, we evaluated 29 human sarcoma specimens for expression of IGF-1 receptor, IGF-1, and IGF-2 by competitive binding and reverse-transcription polymerase chain reaction (RT-PCR) techniques. Twelve of 29 sarcomas examined by RT-PCR and 13 of 25 examined by affinity-binding studies expressed IGF-1 receptor levels equal to or greater than levels determined in the IGF-responsive MCF-7 breast carcinoma cell line. DNA amplification of the IGF-1 receptor gene was not identified in this group of sarcomas that expressed high levels of IGF-1 receptor. Evaluation of IGF ligand expression by RT-PCR revealed that 22 of 28 sarcomas expressed IGF-1 levels comparable to or above those of the RPMI 7666 control line, and 17 of 27 sarcomas expressed significant levels of IGF-2 compared with the NCI H69 control cell line. These results suggest that autocrine/paracrine regulatory mechanisms might be responsible for the growth of some sarcomas.

Base Sequence↗
PubMed1995

HH2A, an immortalized bovine mammary epithelial cell line, expresses the gene encoding mammary derived growth inhibitor (MDGI).

We have established and partially characterized a spontaneously immortalized bovine mammary epithelial cell line, designated HH2a. The cells express the gene encoding for mammary derived growth inhibitor (MDGI) when grown on released collagen gels in the presence of lactogenic hormones. This is the first report of a cell line that expresses MDGI. Immunohistochemical studies showed that HH2a cells contain keratin intermediate filaments and desmosomes. When plated on confluent monolayer of live fibroblasts, HH2a cells extensively contacted with fibroblasts. When embedded in the collagen gels, they rearranged themselves to produce three-dimensional duct-like outgrowths extending into the matrix. The HH2a cell line should be useful in investigations of the roles of cell-cell and cell-extracellular interactions in regulation of breast epithelial cell proliferation, and of the hormonal regulation of MDGI gene expression.

Animals↗
PubMed1995

Sensing of extracellular Ca2+ by parathyroid and kidney cells: cloning and characterization of an extracellular Ca(2+)-sensing receptor.

The ability of the parathyroid cell to sense minute fluctuations in the extracellular ionized calcium concentration (Ca2+ o) is essential for maintaining mineral ion homeostasis. However, the mechanism(s) through which the parathyroid cell and other cells recognize and respond to changes in Ca2+ o has remained unclear. We recently isolated a cDNA encoding a Ca2+ o-sensing receptor from bovine parathyroid using expression cloning in Xenopus laevis oocytes. The receptor shows pharmacologic properties that are almost identical to those of the receptor on the parathyroid cell and, like the latter, stimulates phospholipase C in a G-protein-dependent manner. The amino acid sequence of the cloned receptor deduced from this cDNA predicts a protein with a molecular mass of 121 kd, which has three principal structural domains. The first is a 613 amino acid, putatively extracellular amino terminus which has several regions rich in acidic amino acids that may potentially be involved in binding Ca2+ and other polycationic agonists. The second comprises seven membrane-spanning segments that are characteristic of the superfamily of G-protein-coupled receptors, and the third is a 222 amino acid cytoplasmic tail. Transcripts for this Ca2+ o-sensing receptor are present in the parathyroid as well as in the kidney, thyroid, and brain. We next investigated the hypercalcemic disorders, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, as possible examples of inherited abnormalities in this Ca2+ o-sensing receptor, since both disorders show abnormal Ca2+ o-sensing and/or handling in the kidney and parathyroid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Regulation of IGFBP-3 expression in breast cancer cells and uterus by estradiol and antiestrogens: correlations with effects on proliferation: a review.

This paper reviews actions of antiestrogens on IGF physiology, and discusses the potential significance of the recent observations that (i) effects of antiestrogens on the uterus are correlated with their effects on uterine IGF-I and IGFBP-3 gene expression, and that (ii) the potent antiestrogen and growth inhibitor ICI 182,780 induces autocrine production of IGFBP-3 by estrogen receptor-positive breast cancer cells, while the growth stimulatory action of estradiol is associated with suppression of IGFBP-3 expression.

Breast Neoplasms↗
PubMed1995

Cloning and functional characterization of extracellular Ca(2+)-sensing receptors from parathyroid and kidney.

Parathyroid cells recognize and respond to (i.e., "sense") minute perturbations in the extracellular ionized calcium concentration (Ca2+o), but the mechanisms underlying this process have remained obscure. Recently, we employed expression cloning in Xenopus laevis oocytes to isolate a cDNA coding for a Ca2+o-sensing receptor from bovine parathyroid. Like the native receptor, the cloned Ca2+o-sensing receptor stimulates phospholipase C (PLC) in a G-protein-dependent manner with a nearly identical pharmacological profile. Its deduced amino acid sequence confirms that it is a member of the superfamily of G-protein-coupled receptors (GPR). Transcripts for the receptor are expressed in parathyroid and other tissues that sense Ca2+o (viz., kidney and thyroidal C-cells) as well as those that have no known role in extracellular Ca2+ homeostasis, such as the brain. The availability of the cDNA clone for the Ca2+o-sensing receptor made it possible to test the hypothesis that mutations in the gene encoding the human homolog of the receptor cause inherited disorders of mineral ion metabolism. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are, in fact, caused by mutations that reduce the activity of the receptor when they are present in the heterozygous and homozygous states, respectively. In contrast, we have subsequently discovered a family in which a form of autosomal dominant hypocalcemia results from an activating mutation in the receptor gene. The Ca2+-sensing receptor, therefore, permits Ca2+o to play a "hormonelike" role as an extracellular first messenger in addition to its well described role as an important intracellular second messenger.

Amino Acid Sequence↗
PubMed1995

The cloning of extracellular Ca(2+)-sensing receptors from parathyroid and kidney: molecular mechanisms of extracellular Ca(2+)-sensing.

The parathyroid cell detects changes in the extracellular ionized calcium concentration (Ca2 + o) with exquisite sensitivity, but the mechanisms through which it senses Ca2 + o have remained obscure. Recently, we isolated a cDNA encoding a Ca2 + o-sensing receptor from bovine parathyroid using expression cloning in Xenopus laevis oocytes. The expressed receptor stimulates phospholipase C and has a pharmacological profile almost identical to that of the native receptor. Furthermore, its deduced amino acid sequence confirms that it belongs to the superfamily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid and other tissues sensing Ca2 + o (e.g., kidney and thyroidal C-cells) as well as those not known to be involved in Ca2+ homeostasis (viz., in the brain). We have also shown that mutations in the receptor cause three inherited disorders of calcium metabolism: Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) result from inactivating mutations, when present in the heterozygous and homozygous states, respectively, whereas an autosomal dominant form of hypocalcemia is due to an activating mutation. Thus this Ca2 + o-sensing receptor permits Ca2+o to act as an extracellular, first messenger in addition to its better known role as an intracellular second messenger.

Animals↗
PubMed1995

Molecular mechanisms underlying the sensing of extracellular Ca2+ by parathyroid and kidney cells.

Mineral ion homeostasis in mammalian species is maintained by a complex mechanism comprising sensors of the extracellular calcium concentration (Ca2+0) (i.e. parathyroid cells) as well as effectors that modify their translocation of mineral ions into and out of the extracellular fluid (e.g. kidney) in response to calciotropic hormones. Indirect evidence accumulated over the past decade suggested that parathyroid cells sense Ca2+0 through a cell surface receptor coupled to intracellular second messenger systems via one or more guanine nucleotide regulatory (G) proteins. More recently, Brown et al. employed expression cloning in Xenopus laevis oocytes to isolate a cDNA encoding a Ca2+0-sensing receptor from bovine parathyroid. The expressed receptor activates phospholipase C in a G-protein dependent manner and shows pharmacological properties almost identical to those of the native parathyroid receptor. Agonists for the receptor include not only divalent cations (e.g. Ca2+ and Mg2+) but also trivalent cations and even organic polycations such as neomycin. The deduced amino acid sequence of the cloned receptor confirms that it is a member of the superfamily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid as well as in kidney, thyroid and brain. Therefore, this receptor may mediate the sensing of Ca2+0 not only by parathyroid cells but also by other tissues directly regulated by Ca2+0 (e.g. the thyroidal C cells and certain kidney cells) as well as those not currently known to be involved in calcium homeostasis (viz. in the brain).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Extraosseous Ewing's sarcoma.

Extraosseous Ewing's sarcoma is an undifferentiated round-cell sarcoma that is indistinguishable histologically from Ewing's sarcoma of bone. Despite this similarity, it has been accepted as a distinct clinicopathologic entity. The authors describe a 53-year-old man who presented with extraosseous Ewing's sarcoma of the left subcostal chest wall. The lesion was demonstrated by radiography and computed tomography and confirmed by pathological examination.

Humans↗
PubMed1994

Somatostatin analogue octreotide enhances the antineoplastic effects of tamoxifen and ovariectomy on 7,12-dimethylbenz(alpha)anthracene-induced rat mammary carcinomas.

The efficacy of tamoxifen and ovariectomy in the management of breast cancer is limited by the resistance of many neoplasms to these endocrine therapies and by the fact that initially responding tumors often escape from control during long-term treatment. We evaluated the effect of coadministration of the somatostatin analogue octreotide, which has single agent activity in several in vivo and in vitro breast cancer models, on the antineoplastic actions of tamoxifen and ovariectomy on 7,12-dimethylbenz(alpha)anthracene-induced mammary tumors. Rats received tamoxifen (0.5 mg/kg twice weekly s.c.), octreotide (10 micrograms/kg/h for 6 weeks by osmotic minipump), or the combination 7 weeks following 7,12-dimethylbenz(alpha)anthracene administration. The number of tumors per animal and the sum of the volumes of palpable tumors per animal were significantly less in the combination treatment than in the others. In ovariectomized rats the marked regression of established tumors in the initial 4 weeks after ovariectomy was frequently followed by tumor regrowth. However, continuous infusion of octreotide (50 micrograms/kg/h for 6 weeks postovariectomy) significantly (P < 0.01) suppressed this regrowth. Our data suggest that octreotide enhances the antitumor effects of tamoxifen or ovariectomy in the 7,12-dimethylbenz(alpha)anthracene mammary cancer model.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1994

Enhancement of tamoxifen-induced suppression of insulin-like growth factor I gene expression and serum level by a somatostatin analogue.

Mitogenic responsivity of many neoplasms to IGF-I has been detected in a variety of in vivo and in vitro experimental systems. This has led to the proposal that pharmacological reduction of IGF-I bioactivity might represent a novel non-cytotoxic palliative therapy. We recently reported that tamoxifen, a commonly used antiestrogen antineoplastic agent, significantly suppresses IGF-I gene expression and serum IGF-I levels. We report here that the somatostatin analogue octreotide, previously demonstrated to reduce acromegalic levels of IGF-I towards normal, decreased serum IGF-I to 70 +/- 4% (mean +/- SD) of control values and hepatic IGF-I expression to 65 +/- 10% of control values in a short-term non-acromegalic rat model. Tamoxifen reduced serum IGF-I to 74 +/- 12% of control values and hepatic IGF-I expression to 46 +/- 9% of control values in this model, but the combination of octreotide and tamoxifen reduced serum IGF-I concentration to 49 +/- 10% of control values and hepatic IGF-I gene expression to 12 +/- 9% of control values. The levels of serum IGF-I and hepatic IGF-I gene expression were significantly less in animals treated with the combination of octreotide and tamoxifen than in animals treated with either agent alone (p < .01). This combination represents a novel pharmacological strategy for suppressing IGF-I gene expression that may be relevant to the design of clinical trials.

Animals↗
PubMed1994

Uterotrophic actions of estradiol and tamoxifen are associated with inhibition of uterine insulin-like growth factor binding protein 3 gene expression.

We have recently shown that uterine insulin-like growth factor I (IGF-I) gene expression is up-regulated by tamoxifen, a uterotrophic partial antagonist to the estrogen receptor, but down-regulated by the complete estrogen receptor antagonist ICI 182780, which causes uterine involution. This result is consistent with prior reports indicating that the uterotrophic effects of estradiol are mediated at least in part by estradiol-stimulated uterine IGF-I gene expression. We demonstrate here that the uterotrophic agents estradiol and tamoxifen each suppress expression of the IGF binding protein 3 (IGFBP-3) gene in uterus to less than one-third of control values, while oophorectomy or administration of the complete estrogen receptor antagonist ICI 182780, both of which result in uterine involution, are associated with a greater than 3-fold stimulation of uterine IGFBP-3 gene expression. The data reveal a negative correlation between uterine weight and uterine IGFBP-3 gene expression as well as reciprocal regulation by estradiol of expression in uterus of the genes encoding IGF-I and IGFBP-3. In vitro, IGFBP-3 protein accumulation in media conditioned by primary uterine cultures was decreased by estradiol treatment and increased by ICI 182780 treatment. Together, these observations provide a novel mechanism by which estradiol and antiestrogens modulate uterine IGF-I physiology that is consistent with the view that the mitogenic activity of IGF-I is reduced in the presence of IGFBP-3. The uterotrophic toxicity of chronic estradiol or tamoxifen treatment may be causally related to both the inhibition of uterine IGFBP-3 expression and the stimulation of uterine IGF-I expression by these compounds.

Animals↗
PubMed1994

Metastatic behavior of the RIF-1 murine fibrosarcoma: inhibited by hypophysectomy and partially restored by growth hormone replacement.

BACKGROUND: We recently demonstrated that hypophysectomy profoundly inhibits metastatic behavior in the MGH-OGS murine osteosarcoma model and speculated that this effect is related at least in part to ablation of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis. PURPOSE: In this study, we determined whether the administration of GH to animals rendered GH and IGF-I deficient by hypophysectomy attenuates the inhibitory effects of hypophysectomy on metastatic behavior. METHODS: Metastatic behavior was assayed by counting visible metastases in lungs 3 weeks after tail vein injection of RIF-I fibrosarcoma cells to control mice (n = 29), hypophysectomized mice (n = 19), and hypophysectomized mice administered 0.05 microgram/g body weight recombinant human GH twice daily (n = 21). RESULTS: Twenty of 21 hypophysectomized mice receiving GH, eight of 19 hypophysectomized mice not receiving GH, and 26 of 29 controls had grossly visible pulmonary metastases 3 weeks after intravenous injection of 5 x 10(5) cells; mean numbers +/- SD of gross metastases were 38.4 +/- 11.3, 6.4 +/- 2.2, and 13.1 +/- 2.8 in the three groups, respectively. The presence (P < .005, chi-square test) and number (P = .0003, Mann-Whitney U test) of metastases were significantly reduced in hypophysectomized hosts compared with control hosts and were significantly higher in hypophysectomized, GH-replaced hosts compared with hypophysectomized hosts (P < .001, chi-square test; P = .011, Mann-Whitney U test), while the difference in presence and extent of metastases between control and hypophysectomized, GH-replaced hosts was not statistically significant. CONCLUSIONS: These data support the hypothesis that the status of the host with respect to GH and/or GH-dependent factors such as IGF-I influences the metastatic behavior of certain neoplasms. IMPLICATIONS: Our results raise the possibility that compounds that reduce GH output or interfere with GH action, such as somatostatin analogues, GH antagonists, IGF antagonists, and GH-releasing hormone antagonists, may suppress metastatic behavior of certain neoplasms.

Animals↗
PubMed1993

Insulin-like growth factor I gene expression in the uterus is stimulated by tamoxifen and inhibited by the pure antiestrogen ICI 182780.

Estrogen-induced uterine insulin-like growth factor I (IGF-I) expression has been demonstrated to mediate at least in part the uterotrophic action of estradiol. We studied the effects of tamoxifen, a partial antagonist to the estrogen receptor widely used in the treatment of breast cancer, and ICI 182780, a pure antagonist to the estrogen receptor, on uterine weight and uterine IGF-I gene expression in the rat. Tamoxifen increased uterine weight to 125% of control values and doubled uterine IGF-I expression. In contrast, ICI 182780 reduced uterine weight to 60% of control and uterine IGF-I gene expression to 13% of control. These results demonstrate for the first time that uterine IGF-I expression is a molecular marker that correlates with the effects of partial agonists and antagonists to the estrogen receptor on the uterus. Furthermore, the induction of uterine IGF-I expression by tamoxifen provides a molecular mechanism to account for the uterotrophic effects which are commonly seen with tamoxifen therapy and which have been associated with endometrial neoplasia.

Animals↗