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Biomedical subjects

R Hoffman

Publications and source records attributed to R Hoffman.

At least 217 records · Page 12Linked to original sources
PubMed1992

Hypolipidemic drugs reduce lipoprotein susceptibility to undergo lipid peroxidation: in vitro and ex vivo studies.

Oxidized LDL, which has been discovered in vivo in areas of proximity to the atherosclerotic lesion, has been shown to enhance macrophage cholesterol accumulation. We studied the anti-oxidant potential of pravastatin, bezafibrate and cholestyramine in 18 patients with hypercholesterolemia. In addition, we examined the electrophoretic mobility and the uptake of LDL by macrophages before and after drug therapy. Pravastatin lowered plasma levels of LDL cholesterol by 57%, cholestyramine by 27% and bezafibrate by 25%. Pravastatin and bezafibrate also altered the composition of LDL as evidenced by the reduction of its cholesterol/apo B100 ratio. Pravastatin and bezafibrate reduced plasma triglyceride levels by 45% and 25%, respectively, whereas cholestyramine raised plasma triglyceride concentrations by 28%. LDL propensity for in vitro oxidation was analyzed following lipoprotein incubation with 10 microM copper ions and determination of LDL malondialdehyde (MDA), peroxides (PD) and conjugated dienes (CD) content. All drugs inhibited the susceptibility to in vitro oxidation of LDL isolated after drug therapy in comparison to LDL isolated before commencing drug therapy. Pravastatin reduced MDA content by 22%, PD by 18% and CD by 20%. Cholestyramine reduced LDL content of MDA by 41%, PD by 25% and CD by 63%. Bezafibrate reduced MDA by 41%, PD by 38% and CD by 45%. LDL vitamin E content was reduced after treatment with bezafibrate, pravastatin and cholestyramine by 49%, 36% and 8%, respectively. The electrophoretic mobility of LDL after all drug therapies was reduced in comparison to LDL obtained before therapy. Macrophage uptake of LDL assessed by either the cellular cholesterol esterification rate or by lipoprotein degradation was not affected by drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856).

Temozolomide (CCRG 81045: M&B 39831: NSC 362856) is an analogue of mitozolomide displaying similar broad spectrum activity in mouse tumours, but showing considerably less myelosuppression in the toxicology screen. Temozolomide was initially studied intravenously at doses between 50-200 mg m-2 and subsequently was given orally up to 1,200 mg m-2. A total of 51 patients were entered on the single dose schedule. Temozolomide exhibits linear pharmacokinetics with increasing dose. Myelotoxicity was dose limiting. Experimentally, temozolomide activity was schedule dependent and therefore oral administration was studied as a daily x 5 schedule between total doses of 750 and 1,200 mg m-2 in 42 patients. Myelosuppression was again dose limiting. The recommended dose for Phase II trials is 150 mg m-2 po for 5 days (total dose 750 mg m-2) for the first course, and if no major myelosuppression is detected on day 22 of the 4 week cycle, the subsequent courses can be given at 200 mg m-2 for 5 days (total dose 1 g m-2) on a 4 week cycle. Mild to moderate nausea and vomiting was dose related but readily controlled with antiemetics. Clinical activity was detected using the 5 day schedule in four (2CR, 2PR; 17%) out of 23 patients with melanoma and in one patient with mycosis fungoides (CR lasting 7 months). Two patients with recurrent high grade gliomas have also had partial responses. Temozolomide is easy to use clinically and generally well tolerated. In the extended Phase I trial temozolomide only occasionally exhibited the unpredictable myelosuppression seen with mitozolomide.

Adult↗
PubMed1992

Animal models for human hematopoiesis.

Despite seminal contributions provided by in vitro studies to the field of hematopoiesis, our present knowledge of mammalian lymphohemopoiesis and the mechanisms governing differentiation and self-renewal of hematopoietic stem cells has been derived in most part from elegant in vivo studies. The inability to apply such an approach to the examination of the human hematopoietic system is the primary reason why several aspects of human hematopoiesis including human stem cell biology are still poorly understood. To overcome the inability to probe human hematopoiesis in vivo, researchers have "humanized" animals via the transplantation of human hematopoietic progenitor cells and other tissues in an attempt to create human-animal chimera suitable for investigating human lymphohematopoiesis in vivo. To date, several of these "humanized" animal models have been developed. During their relatively short existence, human-animal models have contributed substantially to the field of experimental hematology. The development, peculiarities, shortcomings, and applications of these animal models as well as their potential use in exploring the field of human lymphohematopoiesis are the focus of this review.

Animals↗
PubMed1992

Left posterior hemiblock related to an interventricular septum tumour. First case in the literature.

A 22-year-old man who engaged in intense and regular physical exercise complained of atypical chest pain. The only remarkable abnormality found in the routine clinical work-up was a left posterior hemiblock. The echocardiogram and the magnetic resonance imaging (MRI) study showed a tumour in the posterior and superior aspect of the interventricular septum where the posterior fascicle of the left bundle is located. It was interpreted that the left posterior hemiblock was produced by the tumour.

Adult↗
PubMed1992

Human hematopoietic stem cell adherence to cytokines and matrix molecules.

The hematopoietic microenvironment is a complex structure in which stem cells, progenitor cells, stromal cells, growth factors, and extracellular matrix (ECM) molecules each interact to direct the coordinate regulation of blood cell development. While much is known concerning the individual components of this microenvironment, little is understood of the interactions among these various components or, in particular, the nature of those interactions responsible for the regional localization of specific developmental signals. We hypothesized that cytokines act together with ECM molecules to anchor stem cells within the microenvironment, thus modulating their function. In order to analyze matrix-cytokine-stem cell interactions, we developed an ECM model system in which purified stem cell populations and plastic-immobilized individual proteins are used to assess the role of various matrix molecules and/or cytokines in human hematopoietic cell development. Analysis of these interactions revealed that a single ECM protein, thrombospondin, in conjunction with a single cytokine (e.g., c-kit ligand), constitutes a developmental signal that synergistically modulates hematopoietic stem cell function.

Antigens, CD↗
PubMed1992

Recombinant GM-CSF/IL-3 fusion protein: its effect on in vitro human megakaryocytopoiesis.

An evaluation of the effectiveness of a genetically engineered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin 3 (IL-3) fusion protein (FP) as a means of delivering cytokine combinations to megakaryocyte (MK) progenitor cells was performed, utilizing a serum-depleted clonal assay system and a long-term bone marrow culture system. The effects of the FP, alone and in combination with a variety of other cytokines, on the primitive MK progenitor cell, the megakaryocyte burst-forming unit (BFU-MK), and the more differentiated megakaryocyte colony-forming unit (CFU-MK) were assessed. Subpopulations of bone marrow cells (CD34+ DR- for BFU-MK and CD34+ DR+ for CFU-MK) served as sources of these two classes of MK progenitor cells. The FP was equivalent to a combination of optimal concentrations of GM-CSF and IL-3 in promoting both the number and size of BFU-MK-derived colonies. The GM-CSF/IL-3 combination, however, promoted the formation of far greater CFU-MK-derived colonies than did the FP alone. The size of MK colonies formed in the presence of the FP or GM-CSF/IL-3 was similar. The ability of the FP to stimulate BFU-MK- but not CFU-MK-derived colony formation was also further augmented by the addition of interleukin 1 alpha (IL-1 alpha). The addition of c-kit ligand (KL) increased both FP-stimulated CFU-MK- and BFU-MK-derived colony numbers but only BFU-MK-derived colony size. In addition, the FP alone sustained long-term megakaryocytopoiesis in vitro to a level equivalent to that of the GM-CSF/IL-3 combination and was superior in this regard to either GM-CSF or IL-3 alone. These data indicate that FP is capable of supporting various stages of human megakaryocytopoiesis. We conclude that such genetically engineered molecules as the FP may prove to be effective means of pharmacologically delivering the biological effects of specific cytokine combinations.

Antigens, CD↗
PubMed1992

Treatment of metastatic colorectal carcinoma with a combination of fluorouracil and recombinant interferon alfa-2b: preliminary data of a phase II study.

From March 1990 to January 1991 52 previously untreated patients with metastatic colorectal carcinoma were enrolled in a phase II study with the combination of interferon alfa-2b and fluorouracil (5-FU). 5-FU 750 mg/m2 per day was administered as continuous infusion for 5 days, then weekly in a dose of 750 mg/m2 as IV push injection starting on day 15. Interferon alfa-2b (Intron A, ESSEX Pharma) 9 x 10(6) units was given subcutaneously three times per week. Response to therapy was evaluated after 3 and 6 months. So far, data on response rates and toxicity are available in 32 patients: partial remission, 10 patients (31%); stable disease, nine patients (28%); progressive disease, 12 patients (37%); toxic deaths, two patients (6%). Projected median survival has not been reached after 11 months. In about one third of the patients severe side effects occurred with leukopenia grade 3 and 4, diarrhea, mucositis and septic complications being the clinically most important. We think that this combination is an effective but toxic regimen in advanced colorectal carcinoma. Further studies must reevaluate both the schedule and the doses of the drugs administered.

Adult↗
PubMed1992

Is interleukin 6 the physiological regulator of thrombopoiesis?

Interleukin 6 (IL-6) is a multifunctional cytokine that also influences megakaryocyte (MK) development. To delineate the relationship between IL-6 and thrombopoietin (TPO), the putative physiological regulator of MK maturation, serum IL-6 levels and platelet counts were correlated in various clinical disorders. IL-6 was measured by a [3H] thymidine incorporation assay using the IL-6-dependent B9 cell line; 1 U is approximately equal to 1 pg/ml of a recombinant (r)IL-6 standard. Specificity of the assay was confirmed by neutralizing rIL-6 and selected sera containing IL-6 activity with anti-IL-6 antibody. Samples (n = 120) were obtained from normal individuals and patients with leukemia, myeloproliferative and rheumatologic disorders, solid tumors, and after bone marrow transplantation and chemotherapy. Patients were also grouped as to whether they had an ongoing inflammatory process, that is, an active infection, solid tumor malignancy, or rheumatological disorder. Serum IL-6 levels were 4.6 +/- 1.4 U/ml for normal individuals and ranged up to 14.8 x baseline; moderate increases (greater than 2 x normal) were found in 21.5% of all patients. Whereas only 39% of thrombocytopenic sera (less than 150,000 platelets) had elevated IL-6 levels, 91% of these sera were from patients with an ongoing inflammatory process. Only 29% of the thrombocytotic sera (greater than 400,000) had elevated IL-6 levels, but 86% of these sera were from patients suffering from concurrent inflammation. Overall, 80% of all patients with elevated serum IL-6 had definitive ongoing inflammatory processes. There was no inverse relationship between platelet numbers and IL-6 levels. Thus, the idea that IL-6 is TPO appears doubtful. However, production of IL-6 during inflammation may result in increased platelet numbers and account for the secondary thrombocytosis observed in some patients.

Blood Platelets↗
PubMed1991

Effect of c-kit ligand on in vitro human megakaryocytopoiesis.

An evaluation of the effects of a recombinant, soluble form of the c-kit ligand alone and in combination with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) on the regulation of human megakaryocytopoiesis was performed using a serum-depleted clonal assay system and a long-term bone marrow culture system. The effects of the c-kit ligand on the primitive megakaryocyte (MK) progenitor cell, the burst-forming unit-megakaryocyte (BFU-MK), and the more differentiated colony-forming unit-megakaryocyte (CFU-MK) were determined. The c-kit ligand alone had no megakaryocyte colony-stimulating activity (MK-CSA) but was capable of augmenting the MK-CSA of both GM-CSF and IL-3. The range of synergistic interactions of c-kit ligand varied with the class of MK progenitor cell assayed. In the case of the BFU-MK, the c-kit ligand synergistically augmented the numbers of colonies formed in the presence of IL-3, but not GM-CSF, but increased the size of BFU-MK-derived colonies cloned in the presence of both of these cytokines. However, at the level of the CFU-MK, c-kit ligand synergized with both GM-CSF and IL-3 by increasing both colony numbers and size. Although the c-kit ligand alone exhibited limited potential in sustaining long-term megakaryocytopoiesis in vitro, it synergistically augmented the ability of IL-3, but not GM-CSF, to promote long-term megakaryocytopoiesis. These data indicate that multiple cytokines are necessary to optimally stimulate the proliferation of both classes of MK progenitor cells and that the c-kit ligand plays a significant role in this process by amplifying the MK-CSA of both GM-CSF and IL-3.

Antigens, CD↗
PubMed1991

Selective up-regulation of type II inosine 5'-monophosphate dehydrogenase messenger RNA expression in human leukemias.

The discovery of isozymes (types I and II) of IMP dehydrogenase (IMPDH; EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, has attracted attention as a possible novel approach to cancer diagnosis and selective tumor cell chemotherapy. To elucidate differences in expression and regulation of the two IMPDH isozymes, we examined the steady-state levels of these mRNAs in various types of leukemic cells from patients. Northern blot analysis revealed that type II IMPDH was more active transcriptionally (1.5- to 5.1-fold) in all the leukemic cells examined than in normal lymphocytes, whereas type I expression was similar. The increased expression of type II mRNA in leukemic cells was closely linked with the increase in total IMPDH activity (r = 0.92). When leukemic cells from a patient with chronic granulocytic leukemia in blast crisis were separated into blast-rich and mature leukocyte-rich fractions, the expression of type II mRNA correlated positively with the population of immature leukemic cells, whereas type I expression was unchanged. Treatment of leukemic blasts with 12-O-tetradecanoyl-phorbol-13-acetate for 5 days resulted in a 90% decrease in the expression of type II mRNA with macrophage-like differentiation, while the expression of type I mRNA was relatively stable. These observations suggest that expression of type II IMPDH is stringently linked with immature characteristics of leukemic cells; thus, it should be a selective target for antileukemic chemotherapy.

Cell Differentiation↗
PubMed1991

Further examination of the effects of recombinant cytokines on the proliferation of human megakaryocyte progenitor cells.

The effect of several recombinant cytokines, including interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1 alpha, on megakaryocyte (MK) colony formation by a normal human bone marrow subpopulation (CD34+ DR+), enriched for the MK colony-forming unit (CFU-MK), was studied using a serum-depleted, fibrin clot culture system. IL-3 and GM-CSF, but not IL-6 or IL-1 alpha, stimulated MK colony formation by CD34+ DR+ cells. However, the addition of IL-1 alpha to CD34+ DR+ cultures containing IL-6 resulted in the appearance of CFU-MK-derived colonies, suggesting that IL-6 requires the presence of IL-1 alpha to exhibit its MK colony-stimulating activity (MK-CSA). Addition of neutralizing antibodies to IL-3 and GM-CSF, but not to IL-6 and IL-1 alpha, specifically inhibited the MK-CSA of IL-3 and GM-CSF, respectively. The addition of either anti-IL-6, anti-IL-1 alpha, or anti-IL-3 antisera to cultures containing both IL-6 and IL-1 alpha totally abolished the MK-CSA of the IL-6/IL-1 alpha combination. However, neither anti-IL-3 nor anti-GM-CSF antisera could totally neutralize the additive effect of the combination of IL-3 and GM-CSF on MK colony formation, indicating that these two cytokines act by affecting distinct effector pathways. These results suggest that while IL-3 and GM-CSF can directly affect CFU-MK-derived colony formation, IL-1 alpha and IL-6 act in concert to promote de novo elaboration of IL-3 and thereby promote CFU-MK proliferative capacity.

Antibodies↗
PubMed1991

Simultaneous use of rhodamine 123, phycoerythrin, Texas red, and allophycocyanin for the isolation of human hematopoietic progenitor cells.

The supravital, mitochondrial specific dye Rhodamine 123 (R123) was used in conjunction with three monoclonal antibodies to isolate a population of human bone marrow (BM) cells enriched for hematopoietic progenitor cells. BM cells stained with phycoerythrin-HLA-DR, Texas red-CD34, allophycocyanin-CD15, and R123 were fractionated using four-color immunofluorescence cell sorting. Cells expressing CD34 but not HLA-DR and CD15 (CD34+ HLA-DR- CD15-) were subdivided according to their reactivity with R123 into quiescent, R123 dull (R+) or cycling, R123 bright (R++) subpopulations. Morphological analysis and hematopoietic progenitor cell assays indicated that CD34+ HLA-DR- CD15- R+ cells contained larger numbers of blast cells and colony forming units than CD34+ HLA-DR- CD15- R++ cells. The flow cytometer settings used to accommodate the detection of the R123 fluorescence in combination with that of three other fluorochromes are described.

Antibodies, Monoclonal↗
PubMed1991

Role of protein kinase C in adriamycin-induced erythroid differentiation of K562 cells.

Modulators of protein kinase C (PKC) were used to investigate the role of this enzyme during Adriamycin-induced erythroid differentiation of K562 cells. Adriamycin (0.1 microM) induced erythroid differentiation in 60% +/- 10% of K562 cells. Phorbol myristate-12-acetate, an activator of protein kinase C, was strongly anti-proliferative to K562 cells (IC50, 8 nM) but did not induce erythroid differentiation. Staurosporine inhibited PKC from K562 cells (IC50, 8 nM) and blocked Adriamycin-induced erythroid differentiation, but only at concentrations marginally below those that inhibited proliferation (IC50, 81 nM), 1-(5-Isoquinolinylsulphonyl)-2-methylpiperazine (H-7) inhibited K562 PKC (IC50, 26 microM) but reduced Adriamycin-induced differentiation by less than 50% at concentrations of up to 600 microM. These data argue against a major role for PKC during Adriamycin-induced erythroid differentiation in K562 cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Pregnancy associated with lupus anticoagulant and heparin induced thrombocytopenia: management with a low molecular weight heparinoid.

The management of pregnant patients with coagulopathies and heparin induced thrombocytopenia is difficult and poorly defined. We report the case of a patient who was treated with a low molecular weight heparinoid. The treatment was complicated by the delayed occurrence of thrombocytopenia and a thrombotic event. This is the first report of thrombocytopenia caused by heparinoid. It is possible that this complication could have been avoided by a shorter duration of treatment with heparinoid and the use of Vitamin K antagonists during the second trimester of pregnancy.

Adult↗
PubMed1991

Regulation of de novo and salvage pathways in chemotherapy.

An overview was presented of our approach of inhibition of de novo and salvage pathways in pyrimidine and purine metabolism. 1. Combination of acivicin, an inhibitor of de novo biosynthesis, and dipyridamole, a transport inhibitor, provided synergistic cytotoxicity in hepatoma and colon carcinoma cells. 2. AZT, a competitive inhibitor of the salvage enzyme, thymidine kinase, and 5-FU or MTX provided synergistic cytotoxicity in hepatoma 3924A. In human colon carcinoma HT-29 cells AZT and methotrexate yielded synergistic cytotoxicity and thymidine and hypoxanthine together provided protection from the action of these drugs. 3. These observations are significant because in rat hepatoma 3924A and in human cell lines HT-29, HL-60 and K562 thymidine kinase activity was 16- to 67-fold higher than that of dTMP synthase. Therefore, inhibition of dTMP synthase activity alone may provide poor responses because the salvage pathways can circumvent this block. 4. In leukemic patients treated with tiazofurin, an inhibitor of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, and with allopurinol, which inhibits GPRT activity through raising plasma hypoxanthine levels, synergistic therapeutic results were obtained. The responses in sensitive patients entailed a decrease in IMP dehydrogenase activity and GTP concentration in leukemic cells and down-regulation of the ras and myc oncogenes. The down-regulation of the ras oncogene by tiazofurin through the decrease of GTP concentration has now been shown in K562, HL-60 and hepatoma cells and in patients with chronic granulocytic leukemia in blast crisis. Tiazofurin may be useful in studies on selective depression of the expression of the ras oncogene. 5. In 27 consecutive patients 50% responded positively to tiazofurin treatment. From this group, 10 out of 12 patients (83%) with chronic granulocytic leukemia in blast crisis responded to tiazofurin treatment.

Antimetabolites, Antineoplastic↗