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Biomedical subjects
Publications and source records attributed to P Reizenstein.
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The bromodeoxyuridine (BRDU) labelling of bone marrow cells was studied in 46 subjects. The labelling in 14 patients, mostly untreated, with the myelodysplastic syndrome (MDS) and four lymphoma patients was significantly (p = 0.043) higher (11.38 +/- SE 2.3% S-phase cells) than that of marrow cells (7.18 +/- SE 1.04%) from 14 apparently healthy normal controls and from nine patients with non hematologic disease. Six iron deficiency had numerically but not significantly increased values. Bone marrow samples from MDS-patients showing the highest numbers of cells in the DNA-synthesis phase had the lowest numbers of colonies and clusters in the CFU-C assay (p < 0.03). The data suggest that the DNA-synthesis period is longer in MDS than in controls.
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By using a quantitative RNA-RNA solution hybridisation method, the average number of mdr1 RNA transcripts per cell was measured in total nucleic acid extracts of leukaemic cells from patients with acute leukaemia. The results in different types of leukaemia were (number of patients with detectable mdr1 RNA/total number of patients; median number of transcripts per cell in samples with detectable mdr1 RNA); de novo untreated acute myelocytic leukaemia (AML): 20/44; 0.7, secondary acute myelocytic leukaemia: 8/13; 1.1, acute lymphocytic (ALL) and undifferentiated leukaemia: 5/14; 0.6, relapsed leukaemia: 7/15; 0.7. Forty-six patients with de novo untreated acute leukaemia (AML: n = 34, ALL: n = 12) were evaluable for response to induction chemotherapy. Twelve of 18 patients (67%) with detectable mdr1 RNA levels achieved complete remission compared to 23 of 28 (82%) with undetectable levels (P = 0.40). The remission duration tended to be longer among patients with undetectable mdr1 RNA (P = 0.08). Leukaemic cells were analysed on consecutive occasions in 12 patients. The level of expression increased in four and decreased in two. In conclusion, expression of mdr1 RNA is common in acute untreated leukaemia. However, treatment with cytostatic drugs seems only rarely to increase the proportion of leukaemic cells that express mdr1 RNA. Expression of the mdr1 gene could be one of several equally important factors contributing to drug resistance in acute leukaemia.
The expression and function of neural cell adhesion molecule (NCAM, CD56, Leu19) on leukaemic blasts was investigated. The expression of NCAM was frequent (64%) in 14 studied cases of acute myeloid leukaemia (AML) but not in chronic lymphocytic leukaemia (CLL: 1/3 cases positive) or immunocytoma (IC: no positivity). No correlation with the expression of other AM (intercellular adhesion molecule-1 (ICAM-1), leucocyte function antigen-1 (LFA-1). VLA beta chain) or with AML type, according to FAB classification, was observed. Blocking of NCAM with anti-Leu 19 MoAb on AML targets resulted in a significant decrease of their susceptibility to LAK killing and in inhibition of conjugate formation. In the case of B prolymphocytic leukaemia (B-PLL) which did not express ICAM-1 or LFA-1 but was NCAM+, a complete resistance to LAK activity and lack of conjugate formation was observed. Blocking of NCAM on LAK effectors did not decrease their cytotoxic activity. Our results suggest that NCAM, in the presence of other AM, may have a supportive role in adhesion of leukaemic targets to LAK effectors.
Lipoxins A4 and B4 together with the all-trans lipoxin (LX) isomers were produced by normal human bone marrow cell suspensions after incubation with ionophore A23187. Both LXA4 and LXB4 enhanced the growth of myeloid progenitor cells in semisolid agar in the presence of suboptimal concentrations of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lipoxin A4 at 10(-10) M stimulated the colony formation in 13 out of 15 tested human bone marrows with a mean (+/- SEM) increase of 47 +/- 11% (p = 0.001). A similar stimulatory effect was observed after addition of LXB4 (10(-10) M). The monohydroxyeicosatetraenoic acids 5-, 12- and 15-HETE did not affect colony growth. In addition, LXA4 (10(-8) M) efficiently counteracted the increased colony formation induced by leukotriene C4 (10(-10) M), suggesting an antagonistic relationship between these lipoxygenase products. The results support a role for lipoxins in the regulation of human myelopoiesis.
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Free radicals, intermediates in the tissue damage caused by radiation, are formed, inter alia, in interactions catalyzed by iron, which synergizes with radiation and some cytostatics (anthracyclins) in causing cell damage. Conversely, iron chelators can counteract cell damage. Similarly, antioxidants can slow atherogenesis, caused in part by oxidative stress and free radicals. Cell damage is also prevented by physiological defense systems like superoxide dismutase, against endogenous free radicals formed by granulocytes, monocytes, etc. Iron can thus induce free radicals which cause DNA double strand breaks and oncogene activation. This is suggested by four epidemiological studies suggesting a higher cancer risk in patients with larger iron stores than in those with small iron stores. In addition to its effect on carcinogenesis, iron can also maintain the growth of malignant cells as well as growth of pathogens. Breast cancer cells, for instance, display 5-15 times more transferrin receptors than normal breast tissue. Iron-carrying transferrin is in fact a growth factor. Hyposideremia in patients with cancer or infection is not a paraphenomenon but a functioning defense mechanism ('nutritional immunity'). If this immunity is broken by iron administration, relapses of diseases like tuberculosis, brucellosis, and malaria have been described. While iron-deficiency anemia should of course be diagnosed, treated and if possible prevented, there are good reasons to avoid over-utilization of medicamental iron.
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Autotransplants in leukemia are controversial; their rationale and results have been questioned. Here we consider several issues central to this debate: (1) Are there convincing data to suggest that more intensive therapy increases cures? (2) Are results post-autotransplant a consequence of the transplant, or do they reflect subject-selection and time-to-treatment (time censoring) biases? (3) Does leukemia relapse after an autotransplant develop from persisting leukemia cells in the subject or the graft? (4) Do autotransplants using hematopoietic stem cells from different sources have distinct outcomes? (5) Are immune-mediated anti-leukemia mechanisms likely to prevent relapse after autotransplants? and (6) Can comparably intensive therapy be given without an autotransplant?
Intestinal absorption of calcium from three different labelled calcium preparations (all containing 500 mg elemental calcium) was determined using the whole body retention and urinary excretion of 47Ca in 14 normal subjects. Chewable calcium carbonate tablets showed a significantly (p less than 0.05) better mean minimum absorption of calcium (25.6% in exp. I, 22.8% in exp. II) than calcium given in the form of a lactogluconate/carbonate effervescent tablet, (17%), but similar to calcium in a chloride solution (24.7%). The minimum calcium absorption varied from 85 to 128 mg. All the preparations were taken with standardized low calcium test meals.
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The expression of adhesion molecules on blasts from 14 patients with acute myeloid leukemia (AML) was investigated by immunofluorescence and flow cytofluorometry. All tested blast populations expressed CD18/CD11a complex [leukocyte function antigen-1 (LFA-1)] and CD29 (very-late antigen (VLA)) and the majority were positive for CD54 [intercellular adhesion molecule-1 (ICAM-1), 78.6%] and CD56 [neural cell adhesion molecule (NCAM), 64.3%]. The expression of two other alpha chains of CD18/CD11b and CD11c varied considerably (64.3% and 42.8% of positive cases, respectively). Only one case (AML-M4) showed a weak expression of the activated platelet antigen CD41b. None of the tested blasts expressed the vitronectin receptor (CD61/CD51). No significant correlation between the expression of adhesion molecules and the FAB type of leukemia could be found. All tested blast populations were completely resistant to NK-mediated cytotoxicity and relatively resistant to LAK-mediated cytotoxicity in the standard 51Cr release assay. While no statistically significant correlation of the results in cytotoxicity assays with the expression of adhesion molecules or the expression of HLA-DR antigen could be observed, 2 out of 3 completely resistant cases lacked ICAM-1. These results show that even leukemic blasts which express all of the tested adhesion molecules can still be resistant to LAK-mediated cytotoxicity.