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Biomedical subjects

M Pollak

Publications and source records attributed to M Pollak.

At least 19 recordsLinked to original sources
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

Tamoxifen attenuates pulsatile growth hormone secretion: mediation in part by somatostatin.

Tamoxifen, a partial competitive antagonist to the estrogen receptor, is a potent inhibitor of the proliferation of experimental mammary carcinoma in the rat and is widely used clinically in the treatment of breast cancer. Blockade of estrogen receptors present on neoplastic cells represents the classic mechanism of action of tamoxifen, but the drug has a variety of other actions that may contribute to its antiproliferative properties. While it is recognized that estrogens play an important role in modulating pulsatile GH release, the effect of antagonists to sex steroid receptors on GH secretory dynamics has not previously been described. In the present study we examined the effect of tamoxifen on pulsatile GH secretion in free-moving adult male and female rats. The drug, when administered in a manner previously shown to be associated with antineoplastic activity, caused a marked suppression of the amplitude of spontaneous GH secretory bursts and significantly reduced mean 6-h plasma GH levels in both sexes compared to those in their respective peanut oil-injected controls. Inhibition of spontaneous GH pulses persisted for up to 7 weeks after tamoxifen administration in both sexes. Immunoneutralization of endogenous somatostatin in tamoxifen-treated male rats completely restored both GH pulse amplitude (121.6 +/- 9.5 vs. 62.5 +/- 13.5 ng/ml in tamoxifen-treated rats given normal sheep serum; P less than 0.02) and mean 6-h plasma GH levels (53.3 +/- 6.6 vs. 17.9 +/- 3.6 ng/ml in normal sheep serum-treated rats; P less than 0.01) to levels observed in our peanut oil-injected controls. These results demonstrate that 1) tamoxifen has potent inhibitory effects on pulsatile GH secretion; and 2) the blunting of GH pulse amplitude by tamoxifen is mediated at least in part by increased release of endogenous somatostatin. These findings motivate further investigation of the clinical significance of tamoxifen-induced suppression of GH secretion in relation to the antineoplastic activity of this commonly used drug.

Activity Cycles↗
PubMed1991

Trimetrexate in untreated and previously treated patients with metastatic breast cancer: a Cancer and Leukemia Group B study.

Twenty-two patients with previously untreated metastatic breast cancer and nineteen patients with refractory metastatic breast cancer were treated with trimetrexate (TMTX). Patients received TMTX 8 mg/m2/day if previously treated or 12 mg/m2/day if previously untreated, both given by intravenous bolus days 1-5, every 21 days. None of the patients previously treated for metastatic disease responded to TMTX. There was one partial responder among the 22 patients with previously untreated metastatic disease. The primary toxicity was hematologic and occurred more frequently in patients with a pleural effusion, low serum protein or albumin, or poor performance status. There were three toxic deaths. The study for previously untreated patients required cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) after 4 cycles of TMTX. This study design for previously untreated patients allows the Cancer and Leukemia Group B (CALGB) to prospectively evaluate the activity of new agents in "chemotherapy-sensitive" metastatic breast cancer.

Antineoplastic Agents↗
PubMed1991

Interferon-induced modulation of epidermal growth factor-stimulated growth of a human breast tumor cell line.

We have determined that interferon-alpha (IFN-alpha) and IFN-gamma inhibit the growth of a human breast tumor cell line, S4, in vitro. Cells were more sensitive to the antiproliferative effects of low-dose IFN-gamma than IFN-alpha. As the growth of the S4 cell line is enhanced by epidermal growth factor (EGF), we examined the effect of IFN on EGF-dependent growth of S4 cells. Cells plated in 2.5% serum alone failed to grow. EGF stimulated these cells to grow more than twofold. IFN substantially attenuated the EGF-stimulated growth of S4 cells. Binding of EGF to its receptor was unaffected by pretreatment of cells with IFN-alpha. However, a 24-h exposure of cells to IFN-gamma significantly increased the number of EGF receptors on S4 cells. Internalization of the EGF receptor was unaffected by IFN treatment. Binding remained elevated through 4 days of IFN-gamma exposure. Scatchard analysis of receptor binding data revealed that IFN-gamma increased the number of binding sites without changing the affinity of the receptor for its ligand. These results demonstrate that IFN inhibits EGF-stimulated growth of a breast tumor cell line and suggest that the antiproliferative effect of IFN may be due, in part, to its interaction with growth factor-initiated pathways.

Breast Neoplasms↗
PubMed1991

The ability of suramin to block CD4-gp120 binding is reversed in the presence of albumin.

We have shown that suramin can directly inhibit the binding of the human immunodeficiency virus type 1 gp120 envelope protein to immobilized CD4, thus helping to explain the previously described antiviral properties of suramin. However, physiological concentrations of serum albumin significantly attenuated suramin's antiviral effects, suggesting that only free suramin has antiviral properties. Reported discrepancies between in vitro and clinical activities of suramin may be due to differences between free suramin levels in experimental assays and those achievable clinically.

Animals↗
PubMed1991

A mathematical model describing consequences of abnormally high levels of epidermal growth factor receptor on the proliferation of neoplastic cells.

Recent laboratory and clinical data suggest that some human neoplasms exhibit unusually high levels of cell-surface receptors for epidermal growth factor, and that this abnormality is associated with rapid cellular proliferation and poor prognosis. We propose that the existence of an abnormally high number of mitogen receptors is not merely correlated with rapid proliferation but is pathophysiologically responsible for such behavior. Cells with high levels of mitogen receptors may be rendered 'hypersensitive' to mitogenic stimuli, and hence may be stimulated to divide even when ambient mitogen concentrations are at a low 'background' level, insufficient to prompt the division of cells with a normal number of receptors. To investigate this hypothesis further, we have developed a mathematical model that describes proliferative behavior of cells as a function of mitogen concentration and receptor number. The model enables us to simulate the proliferative behavior of cells with various receptor levels at various mitogen concentrations and predicts a growth advantage associated with excess mitogen receptors. Computer simulations based on the model are consistent with previously published experimental data. This work provides support for the view that overexpression of genes encoding normal growth factor receptors can contribute to the inappropriate proliferation of neoplastic cells.

Cell Division↗
PubMed1990

Effect of tamoxifen on serum insulinlike growth factor I levels in stage I breast cancer patients.

Insulinlike growth factor I (IGF-I) has been shown to be a potent mitogen for breast cancer cells in vitro, and IGF-I receptors have been demonstrated on human primary breast neoplasms. In a randomized, placebo-controlled study, we document that administration of the antiestrogen tamoxifen to patients with breast cancer was associated with a statistically significant (P = .002) reduction in the serum level of IGF-I. The mean IGF-I level was 1.4 U/mL in the placebo-treated group and 0.9 U/mL in the tamoxifen-treated group. Because serum IGF-I level is growth hormone (GH) dependent and because data suggest that the pubertal surge in GH and IGF-I levels is sex steroid dependent, we speculate that the mechanism underlying our observation may involve blockade by tamoxifen of estrogen action in the hypothalamic-pituitary axis. We conclude that tamoxifen treatment reduces IGF-I levels and that this reduction may contribute to the therapeutic effect of the drug.

Aged↗
PubMed1990

Suramin blockade of insulinlike growth factor I-stimulated proliferation of human osteosarcoma cells.

The polyanionic compound suramin is currently being evaluated for antineoplastic activity. On the basis of previous in vitro studies, it has been suggested that the mechanism of action of suramin may be related to its ability to attenuate the mitogenic effects of peptide growth factors, such as platelet-derived growth factor and epidermal growth factor. We recently reported that MG-63 human osteosarcoma cells are mitogenically responsive to insulinlike growth factor I (IGF-I). We now demonstrate for the first time that suramin interferes with the interaction between IGF-I and its receptor and abolishes in vitro IGF-I-stimulated proliferation of these osteosarcoma cells. The fact that cell proliferation resumes when suramin is removed indicates that this is not a cytotoxic effect. We conclude that IGF-I should be added to the list of growth factors whose bioactivity can be attenuated by suramin and that clinical studies of suramin and its analogues are indicated in IGF-I-receptor-positive malignancies such as osteogenic sarcoma.

Affinity Labels↗
PubMed1990

Mitomycin C and mitoxantrone chemotherapy for advanced breast cancer: efficacy with minimal gastrointestinal toxicity and alopecia.

In an attempt to examine the possibility of decreased toxicity in patients with advanced breast cancer who had not previously received chemotherapy, 33 women were given combination chemotherapy consisting of mitomycin C (10 mg/m2) every 6 weeks and mitoxantrone (6 mg/m2) every 3 weeks. The patients had predominantly visceral disease and received a median of two cycles of therapy. Of the 32 evaluable subjects, 15 (47%) achieved a partial response lasting a median of 7 months. Hematological toxicity was generally mild, although there were two episodes of sepsis. One patient developed hemolytic-uremic syndrome, and one subject developed pulmonary fibrosis, both presumably attributable to treatment with mitomycin C. Another patient died of hepatic failure (hepar lobatum). Thus, there were five patients who sustained life-threatening toxicities; this may have been due to the poor performance status and advanced age of some of the patients. Gastrointestinal toxicity and alopecia were minimal. Patient acceptance was high and there was an improvement in symptomatology in the majority of patients. In conclusion, mitomycin C and mitoxantrone chemotherapy is an active drug combination for the treatment of advanced breast cancer that seldom causes significant distressing gastrointestinal side effects or alopecia; however, the duration of response to this regimen appears to be shorter than that obtained with either cyclophosphamide - methotrexate - 5-fluorouracil (CMF) or cyclophosphamide - Adriamycin - 5-fluorouracil (CAF) combination chemotherapy.

Alkylating Agents↗
PubMed1989

Body size and breast cancer prognosis: a statistical explanation of the discrepancies.

A historical cohort of 68 female breast cancer patients from one institution who were enrolled in a multicenter randomized controlled trial between 1971 and 1973 were followed up to the beginning of 1986. Weight and height at the time of mastectomy were transformed into two indices of body size, namely the Quetelet Index and a weight to "ideal weight" ratio. These two indices were analyzed for their relation with overall and disease-free survival, while controlling for the effect of several potential confounding variables. While neither index was linearly related to the hazard of death or recurrence, a significant quadratic (curvilinear) relation was found for both indices and both hazards. In all cases the hazard function was concave up, indicating that not only overweight but also underweight status is predictive of an unfavorable prognosis of breast cancer. This finding offers a possible explanation for the discrepancies among previous studies on this topic.

Adult↗
PubMed1988

Combination chemotherapy with carboplatin and bleomycin for advanced and recurrent head and neck cancer: a phase II study.

Carboplatin is a platinum analogue with activity reported in head and neck cancer. We conducted a phase II trial with 14 patients who had recurrent head and neck cancer. They were treated with carboplatin 300 mg/m2 intravenously (I.V.) and bleomycin 30 units I.V. every 4 weeks. No responses were observed in this group of patients. Dose intensity of carboplatin administration may be an important determinant of response.

Aged↗
PubMed1988

[Psychosocial consequences of HIV infection].

A questionnaire survey of 103 patients of the Paris Pitié-Salpêtrière Hospital measures the changes in family life, work relations and in sexual behaviour occurring after an HIV infection diagnosis. Most patients choose to keep their diagnosis secret, an attitude that places them into a double bind situation. This silence, chosen as a mean of self-protection, prevents patients from making themselves understood and from mobilising the material and psychological help they need.

Acquired Immunodeficiency Syndrome↗