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Biomedical subjects

S Zucker

Publications and source records attributed to S Zucker.

At least 109 records · Page 6Linked to original sources
PubMed1980

Very low density lipoprotein hematopoiesis inhibitor from rat plasma.

Although the stimulatory effect of specific glycoproteins on bone marrow cell proliferation is acknowledged, little attention has been directed toward growth inhibitors. In this report we have explored the role of plasma lipoproteins in regulating the proliferation of hematopoietic cells. Lipoproteins were isolated from the plasma of normal rats and rats with cancer by density gradient ultracentrifugation. Lipoprotein fractions were then added to cell cultures to assess their effect on: 1) erythropoietin (Ep) stimulated rat marrow DNA and protein synthesis, 2) Ep and colony stimulating factor induced marrow colony formation (CFU(E), CFU(C)), and 3) phytohemagglutinin (PHA) stimulated lymphocyte DNA synthesis. The results indicated that very low density lipoproteins (VLDL) completely inhibited CFU(E) and CFU(C) formation. VLDL inhibited (> 80%) the synthesis of DNA by marrow cells cultured with Ep and lymphocytes cultured with PHA. VLDL from rats with Walker-256 cancer had a greater inhibitory effect than normal rat VLDL. Chylomicrons had moderate growth inhibitory effect, and plasma LDL and HDL were inactive. VLDL, however, did not inhibit the proliferation of rat fibroblasts. We conclude that physiologic concentrations of plasma VLDL have a significant inhibitory effect on the proliferation of erythroid, granulocytic and lymphocytic cells. A pathophysiologic role for VLDL in the impairment of erythropoiesis and immune function in cancer is suggested.

Animals↗
PubMed1980

Cancer cell inhibition of erythropoiesis.

In this study we have used tissue culture techniques to explore the mechanism by which metastatic cancer cells in the bone marrow interfere with erythropoiesis. The effect of transplantable Walker-256 (W256) cancer cells on Ep-stimulated erythroid colony formation (CFU-E) in methylcellulose cultures and 59Fe-heme synthesis by rat marrow cells in suspension cultures was studied. The number of CFU-Es per 4 X 10(5) marrow cells decreased by 55% in the presence of 4 X 10(2) cancer cells. Likewise, the stimulatory effect of Ep on normal marrow heme synthesis decreased by 89% when cancer cells were added to marrow cell cultures. By the immobilization of the cancer cells in an agar underlayer, the inhibitory effect of cancer cells on marrow erythropoiesis in an upper methylcellulose layer was demonstrated to be independent of cell contact. The CFU-E growth-inhibitory effect of cancer cells could be attenuated by drugs which interfere with cancer cell protein and DNA synthesis. Although these experiments suggest that cancer cells produce an inhibitor of erythropoiesis, a stable inhibitory factor was not isolated. In similar experiments, rat peritoneal macrophages were also able to inhibit in vitro erythropoiesis. We conclude that cancer cells have the capacity to inhibit erythropoiesis by a mechanism which is independent of cell contact.

Animals↗
PubMed1979

Liproprotein inhibitor of bone marrow cells in tumor-bearing rats.

The role of a plasma inhibitor of erythropoiesis is evaluated in rats with Walker-256 carcinoma (W-256). Plasma from tumor-bearing rats was treated by gel filtration chromatography (Sephadex G-150) and fractions were combined into four pools on the basis of mol. wt. Inhibitory activity was assayed by adding an aliquot of the plasma fractions to normal rat marrow cells which were cultured for 24 hr with and without erythropoietin. 59Fe-heme synthesis, [3H]thymidine DNA synthesis, and 14C-leucine protein synthesis were studied. The results indicated that cultures containing the high mol. wt. pool (greater than 400,000 daltons) had significantly decreased heme, DNA and protein synthesis. This inhibitor also diminished the response to erythropoietin in polycythemic mice. The lower mol. wt. pool stimulated heme synthesis in vitro. To identify the inhibitor further, plasma lipoprotein classes were isolated by density gradient ultracentrifugation. The very low density lipoprotein (VLDL) and chylomicron fractions markedly inhibited DNA, protein and heme synthesis. Low density and high density lipoprotein fractions were inactive. A lipoprotein inhibitor of erythropoiesis was also identified in cancerous ascitic fluid, and to a lesser degree, in normal rat plasma. We suggest that this VLDL inhibitor of marrow erythropoiesis is a contributing factor in the anaemia of cancer.

Animals↗
PubMed1979

Immunologic and coagulation disorders in chlorpromazine-treated patients.

The prevalence of immunologic and coagulation disorders in 75 schizophrenic patients treated with chlorpromazine or other antipsychotic drugs was evaluated. Four groups were studied: Group A, chlorpromazine treatment for more than 2 1/2 years; Group B, chlorpromazine and other antipsychotic drug treatment for more than 2 1/2 years; Group C, chlorpromazine treatment for less than 2 1/2 years; Group D, no chlorpromazine, but other antipsychotic drug treatment. Significant elevation of serum IgM and prolongation of partial thromboplastin time were noted in patients who had long-term chlorpromazine treatment. The latter was caused by a circulating inhibitor resembling that seen with systemic lupus erythematosus. There was a significant correlation between the IgM level versus chlorpromazine dose or duration of treatment and the partial thromboplastin time versus chlorpromazine dose or duration of treatment. In Groups A and B, 63% had a positive antinuclear antibody test (greater than or equal to 1:80), 40% had antibodies to native DNA, and 58% had antibodies to nucleoprotein. These antibodies were negative in the other groups. The percentages of T lymphocytes were below normal in 13 of 41 patients treated with chlopromazine. Twenty of 42 patients in Groups A and B, and none of 28 in Groups C and D had splenomegaly. This study indicates that most patients on long-term chlorpromazine treatment develop one or more immunologic abnormalities.

Adult↗
PubMed1978

IgM inhibitors of the contact activation phase of coagulation in chlorpromazine-treated patients.

In this report we have described three patients with chronic schizophrenia on long-term chlorpromazine therapy who developed asymptomatic IgM inhibitors of the intrinsic phase of blood coagulation. The anticoagulant resulted in decreased measurements of all of the plasma clotting factors in the intrinsic pathway (factors VIII, IX, XI, XII, Fletcher factor and Fitzgerald factor). Using crude coagulation reagents, the serum of these patients interfered with the clot promoting activity of contact product. To determine the relationship between drug therapy and these IgM inhibitors, we have studied nine additional schizophrenic patients on long-term chlorpromazine therapy. All nine chlorpromazine-treated patients had significantly increased levels of serum IgM and asymptomatic inhibitors of coagulation. We conclude that long-term high-dose chlorpromazine treatment of schizophrenic patients results in an increased concentration of IgM which has inhibitory activity in the contact phase of blood coagulation.

Blood Coagulation Disorders↗
PubMed1977

Pathogenesis of anemia in rats with Walker 256 carcinosarcoma.

The purpose of this study was to further clarify the pathophysiology of anemia in malignancy. To accomplish this end a total of 210 normal or splenectomized rats with or without the solid form of Walker 256 carcinosarcoma was studied. In vivo studies demonstrated that in stage I cancer (tumor weight less than 10% of body weight) a slightly shortened red cell survival resulted in a mild degree of anemia. With increasing tumor size, 51Cr red cells mass decreased further, in spite of extramedullary erythropoiesis and a slightly increased incorporation transferrin-bound iron into red cells. Splenectomized rats with stage II cancer developed a more profound degree of anemia associated with a significantly decreased incorporation of 59Fe into red cells. Marrow cell culture studies demonstrated that heme synthesis in response to erythropoietin in stage I cancer was not significantly different from normal, but in rats with stage II cancer (tumor weight greater than 10% of body weight) heme synthesis in response to erythropoietin was markedly decreased. In vitro studies demonstrated that plasma erythropoietin levels were appropriately increased in most rats with transplanted malignancy. These studies indicate that bone marrow heme synthesis in response to erythropoietin is impaired in rats with the anemia of advanced malignancy.

Anemia↗
PubMed1976

Diminished bone marrow responsiveness to erythropoietin in myelophthisic anemia.

The purpose of this study was to examine a mechanism which might explain the diminished erythropoiesis that occurs when tumor cells invade the bone marrow (myelophthisic anemia). To this end we compared 21 patients with neoplastic bone marrow invasion with seven normal subjects. When erythropoietin was added to bone marrow cell cultures from the normal subjects, the baseline rate of heme synthesis for a specific number of marrow erythroid cells increased 65%. In contrast, in patients with greater than 60% of the marrow replaced by tumor, the marrow cell culture response to erythropoietin was 14% above baseline. A significant inverse correlation was noted between the degree of marrow infiltration with tumor and the stimulation of heme synthesis with erythropoietin. It is proposed that marrow invasion with tumor may result in decreased marrow response to erythropoietin, and hence, diminished red cell production.

Adult↗
PubMed1976

Erythropoiesis in chronic renal disease.

The diminished erythropoiesis in the anemia of chronic renal disease has been attributed to three possible factors: (1) decreased erythropoietin production, (2) inhibition of erythropoietin activity, and (3) decreased bone marrow response to erythropoietin. In this report we isolated and evaluated these parameters in 19 patients with chronic renal disease, nine patients with iron-deficiency anemia, and seven control subjects. The results in patients with chronic renal failure were as follows: (1) erythropoietin enhanced heme synthesis in bone marrow cell cultures by 88 +/- 12 per cent in renal failure, as compared to 65 +/- 7 per cent in the control group; (2) plasma erythropoietin activity did not increase appropriately for the degree of anemia; and (3) erythropoietin inhibitor activity in renal failure was not greater than in a control group. In conclusion, the relative failure of erythropoiesis in chronic renal disease appears to be due primarily to decreased production of erythropoietin and not to diminished marrow response to erythropoietin.

Adult↗
PubMed1974

Bone marrow erythropoiesis in the anemia of infection, inflammation, and malignancy.

A major factor in the anemia of infection, inflammation, and malignancy is a relative failure of the bone marrow to increase erythropoiesis in response to a shortened red cell survival. The possible causes for this diminished marrow response are: (a) a reduced production of erythropoietin, or, (b) impaired bone marrow response to erythropoietin. In this report studies were performed on 6 normals, 13 patients with anemia from infection or inflammation, and 18 patients with anemia caused by advanced malignancy. Serum erythropoietin activity was measured using the posthypoxic, polycythemic mouse assay. Assessment of bone marrow response to erythropoietin was made by measuring (59)Fe-heme synthesis in bone marrow suspensions cultured for 3 days with and without the addition of erythropoietin. The results showed that marrow heme synthesis was increased in erythropoietin-treated cultures as compared with saline control cultures by 66+/-8% (mean +/-SE) in normals, 101+/-10% in patients with infection or inflammation, and 31+/-5% in malignancy. Serum erythropoietin levels were consistently diminished relative to expected levels for the degree of anemia in the infection-inflammatory group, but not in malignancy. In these patients, plasma inhibitors to the biological activity of erythropoietin were not detected in vitro. These studies suggest that another factor to consider in the anemia of malignancy is a decreased bone marrow response to erythropoietin. In the anemia of infection-inflammation, marrow response to erythropoietin is normal, but serum levels of erythropoietin are decreased relative to the degree of anemia.

Aged↗