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Biomedical subjects

M Pollak

Publications and source records attributed to M Pollak.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1993

In vivo inhibition of insulin-like growth factor I gene expression by tamoxifen.

Tamoxifen, a partial antagonist to the estrogen receptor, is widely used in the treatment of breast cancer and is currently being evaluated as a breast cancer preventative agent in large-scale clinical trials. Recent clinical research has demonstrated that tamoxifen administration is associated with a reduction of serum insulin-like growth factor I (IGF-I) concentration. We demonstrate here that tamoxifen, when administered in an in vivo experimental system previously used to demonstrate its cytostatic effect on breast cancer cell proliferation, inhibits the expression of the IGF-I gene in common target organs for breast cancer metastasis. Furthermore, while our prior experimental studies have demonstrated an inhibitory effect of tamoxifen on growth hormone output, we show here for the first time that the suppression of IGF-I gene expression associated with tamoxifen administration is in part a consequence of a pituitary-independent action of the drug. Because IGF-I is a potent mitogen for breast cancer cells, this newly described activity of tamoxifen may contribute to its antineoplastic properties, particularly with regard to inhibition of metastasis seen both in animal models and clinically.

Animals↗
PubMed1993

The human insulin-like growth factor-binding protein 4 gene maps to chromosome region 17q12-q21.1 and is close to the gene for hereditary breast-ovarian cancer.

The gene for insulin-like growth factor-binding protein 4 (IGFBP4) codes for a serum protein that binds to the family of insulin-like growth factors and modulates their activity. It has been mapped by in situ hybridization to chromosome region 17q12-q21.1. We have developed a CA-repeat polymorphism from a cosmid clone containing IGFBP4. By linkage analysis, IGFBP4 maps to the chromosome 17q interval THRA1-D17S579. This interval also contains the gene for hereditary breast-ovarian cancer, BRCA1. Genetic recombination between IGFBP4 and BRCA1 places IGFBP4 centromeric to the cancer susceptibility gene and effectively excludes it as a candidate gene for BRCA1. IGFBP4 is, however, one of the closest known centromeric markers for BRCA1; the estimated recombination fraction is 0.015. IGFBP4 and D17S579 together define a 2.8-cM interval that contains BRCA1.

Base Sequence↗
PubMed1993

Suppression of serum insulin-like growth factor-1 levels in breast cancer patients during adjuvant tamoxifen therapy.

Serial IGF-1 levels in patients prior to and during adjuvant tamoxifen (TAM) treatment were followed in a retrospective study. Serum IGF-1 levels were determined by radioimmunoassay in 19 patients taking TAM and 19 controls, matched for age, body weight and other treatments. IGF-1 levels at 2 years were significantly lower in TAM patients (P < or = 0.05) compared to control patients. We observed a significant mean drop from pretreatment to treatment IGF-1 levels by 19.9% in the TAM group (P < or = 0.005), but also noted a mean 11.4% decline in the control group (P < or = 0.025). A subgroup analysis suggested that premenopausal were relatively resistant to the IGF-1 lowering effects of TAM as compared to postmenopausal women.

Adult↗
PubMed1993

Pregnancy complicated by medulloblastoma with metastases to the placenta.

BACKGROUND: Maternal malignancy may complicate as many as one in 1000 pregnancies. Rarely, the tumor may metastasize to the products of conception. We here describe a case of medulloblastoma metastatic to the placenta. CASE: A 21-year-old woman who had previously undergone resection of a posterior fossa medulloblastoma was admitted at 20 weeks' gestation complaining of low back pain. Investigation revealed medulloblastoma metastatic to the bone marrow. The pregnancy was prolonged to 29 weeks' gestation, at which time she was delivered by cesarean. The postoperative course was complicated by coagulopathy, massive bleeding, and pneumonia leading to death. Autopsy showed medulloblastoma metastatic to the bone marrow and placenta. CONCLUSION: Primary intracranial neoplasms may metastasize to the products of conception. The dramatic course of the disease in this patient may suggest that medulloblastoma is responsive to hormonal therapy.

Adult↗
PubMed1992

Inhibition of metastatic behavior of murine osteosarcoma by hypophysectomy.

BACKGROUND: We recently reported that human osteogenic sarcoma cells are mitogenically responsive in tissue culture to insulin-like growth factor I (IGF-I), a mitogen important in the regulation of cellular proliferation of many tissues, including bone. PURPOSE: The present study was designed to determine whether these in vitro observations could be extended to an in vivo experimental system and whether reduction of IGF-I levels by hypophysectomy could inhibit the aggressive metastatic behavior of osteosarcoma. METHODS: We used standard competitive binding and affinity-labeling techniques to characterize the IGF-I-binding sites of MGH-OGS, a model of human osteosarcoma. Radioimmunoassay of serum, preprocessed to remove IGF-binding proteins, was used to quantitate IGF-I levels. In vitro proliferative response of MGH-OGS cells to IGF-I and other pituitary-dependent factors was determined by thymidine-incorporation experiments. In vivo growth of the neoplasm in 12 hypophysectomized C3H mice and in 14 control C3H mice was determined by serial measurements of implanted tumors and by gross and microscopic examination of the lungs for metastases. RESULTS: MGH-OGS exhibited specific binding sites for 1.39 pmol IGF-I per milligram MGH-OGS cellular membrane protein, a concentration similar to that which we previously reported for human osteosarcoma. In tissue culture, MGH-OGS exhibited mitogenic response to IGF-I (P less than .01) but not to other pituitary-dependent factors. Hypophysectomy reduced levels of circulating IGF-I to 15% of control, significantly inhibited local growth of MGH-OGS tumors (increased time for growth to 1 cm3 from 49 to 84 days, P less than .001), and profoundly inhibited metastatic behavior (decrease in mean number of metastases per host from 16 to less than one; P less than .001). CONCLUSIONS: This study is the first to document the profound inhibitory effect of hypophysectomy on the metastatic behavior of an experimental sarcoma. We conclude that the metastatic behavior exhibited by MGH-OGS osteosarcoma is dependent on pituitary factors, and we suggest that the inhibitory effects of hypophysectomy are related, at least in part, to the reduction of IGF-I levels.

Animals↗
PubMed1992

Potential role for somatostatin analogues in breast cancer: rationale and description of an ongoing trial.

Somatostatin analogues such as octreotide have been shown in experimental systems to exhibit antineoplastic activity. Further laboratory and clinical research is needed to clarify the mechanism of action of somatostatin analogues as antineoplastics, and to determine if the encouraging preclinical results will lead to novel endocrine approaches to the treatment of breast cancer.

Aminoquinolines↗
PubMed1992

Impact on the general public of media campaigns against AIDS: a French evaluation.

The article presents the results of the first national survey in a representative sample of the French population of 18 years of age and over (n = 1000; March 1990) about knowledge, attitudes, beliefs and practices toward HIV infection. It focuses on the impact of the media campaigns about AIDS and condom promotion that were initiated since April 1987 by French public health authorities. A total of 53.2% of respondents were able to correctly quote at least one of the slogans of the campaigns and 48.4% felt they have been personally influenced by the campaigns. Respectively 25.4%, 12.1%, and 11.2% declared that the campaigns have made them more concerned of individual risk of HIV infection and prompted them to condom use and HIV testing. Among heterosexually active respondents, 16.9% declared condom use in the past 12 months, age, marital status, level of education, HIV testing and self-acknowledgement of influence of campaigns being the main factors related to condom use in multidimensional analysis. Respondents who recognise having been influenced by campaigns are less likely to believe in HIV transmission through casual contact and to express discriminatory attitudes toward HIV carriers but more likely to support HIV mandatory screening for the general population. The difficulties to properly evaluate media campaigns for AIDS prevention are discussed as well as the complex trade-offs that general public information has to face between promotion of both individual behavioural change and societal support and empathy for HIV carriers and persons with AIDS.

Acquired Immunodeficiency Syndrome↗