Biomedical subjects
Publications and source records attributed to H D Preisler.
Unseparated as well as nonadherent human bone marrow cells produced colonies while suspended within plasma clots contained within diffusion chambers implanted into irradiated mice. The majority of colonies consisted of granulocytes or macrophages. Colony size was significantly increased by the administration of endotoxin prior to implantation of the chambers.
Twenty-three consecutive patients with metastatic carcinoma of unknown primary referred to a medical oncology service over the past two years were studied. In the majority of patients, death occurred within one year of diagnosis and a priamry site of disease was identified at postmortem examination. Of patients who had a primary site identified, findings suggestive of involvement of that site were present during the course of their illness. Survival was greatest in patients with adenocarcinoma histology, with lymph node site of presentation and in those treated with both radiation therapy and chemotherapy, although these differences were not statistically significant. Despite the prolonged survival of a few patients, it is clear that failure to extensively evaluate subtle clinical findings and the lack of efficacious therapy for the malignancies commonly encountered seriously limit the survival of the vast majority of these patients. The identification of new tumor markers and the use of adjunctive chemo-immunotherapy to excisional surgery may ultimately improve to outlook for these patients.
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The migration of specifically sensitized mouse spleen cells following exposure to allogeneic cells (antigen) in vitro was studied. The migration inhibition recorded when sensitized cells were admixed with allogeneic cells in capillary tubes (mix method) was compared to the inhibition observed when allogeneic cells were suspended in the culture chamber media (non-mix method). Specificity as well as a higher degree of migration inhibition were obtained using the mix method, suggesting that this method is superior to the nom-mix method.
Malignant histiocytosis (MH) is a rapidly fatal systemic disease for which there is no adequate therapy. A case of MH with involvement of both eyes resulting in bilateral blindness is presented. Infiltration with malignant cells was seen in the ciliary bodies at autopsy. Attempts at treatment for this complication are discussed.
The clinical characteristics of 10 patients with acute myelogenous leukemia (AML) which developed subsequently to treatment for another neoplasm are described. This disease appears to differ from "spontaneous" AML in being associated with lesser degrees of leukemic infiltration of the marrow and more frequent chromosomal aberrations. Only one of the nine patients who received chemotherapy attained remission status, and the mean and median survivals from the initiation of chemotherapy were 2.7 months and one month respectively. Nine of the 10 patients died as a result of infection. The refractoriness of this form of AML to chemotherapy was borne out by a review of the literature, which revealed only two remissions in 32 treated patients. The implications for the management of this disease are discussed.
A density cut method was used to prepare two subpopulations of bone marrow cells which were enriched (BE) and depleted (BD) respectively of blast cells. Marrow aspirates were obtained from 32 patients, 26 of whom had acute leukaemia. The uptake of a variety of chemotherapeutic agents by these two subpopulations and the acid-soluble ribonucleotide profiles of the populations were compared and significant differences were found in drug uptake by BE and BD subpopulations. For some drugs such as cytosine arabinoside, uptake was greatest by the BE cells, while for 5-azacytidine the BD subpopulation took up the greatest amount of the drug. The preparation of the BE subpopulation also permitted the recognition of several patients with acute leukaemia whose blast cells possess nondetectable levels of ATP, UTP, and GTP components in their acid-soluble fractions. The studies presented demonstrate the necessity of using purified cell populations when characterizing the drug uptake patterns and the soluble ribonucleotide profiles of the leukaemic cells. A simple method for enriching bone marrow aspirates for leukaemic cells is also presented.
The pathophysiology of serially passaged myeloid leukemia of the RFM mouse was studied. The disease was characterized by progressive splenomegaly and infiltration of both marrow and spleen by myeloblasts. The animals became anemic and there was an associated erythroid hyperplasia in the spleen. Leukemic spleen cells obtained from animals early in the course of the leukemia were less malignant than those obtained from preterminal mice. The leukemia is most sensitive to alkylating agents but is also responsive to antimetabolites.
Centrifugal elutriation was used to separate human acute leukemia cells into proliferative and quiescent subpopulations. Ten bone marrow specimens and 5 peripheral blood specimens were subjected to centrifugal elutriations. From each patient, leukemic cell subpopulations were obtained for which the [3H]thymidine labeling index differed by 10- to 30-fold. In 6 of the marrow specimens and in 2 of the peripheral blood specimens, cell subpopulations were obtained for which the labeling index exceeded 20%. In 5 marrow specimens, subpopulations were obtained for which the labeling index exceeded 40%. Preliminary studies of the uptake of 1-beta-D-arabinofuranosylcytosine and 5-azacytidine failed to show any correlation between drug uptake and the proliferative characteristics of the leukemic subpopulations.
A large number of low molecular weight polar cryoprotective agents have recently been found to induce erythroid differentiation of Friend leukemic cells in vitro. The effect of these agents on membrane fluidity in phospholipid vesicles was studied by determining the solid-to-liquid crystalline phase transition using differential scanning calorimetry. Some of the inducing agents studies were found to raise the normal transition temperature (Tc) by a few degrees. All of these agents were found to produce a separate transition at a much higher temperature. Changes in the head group of the phospholipid, the pH, the presence of divalent cations, and the addition of other membrane-active compounds were found to significantly influence the inducing agent's effects on the Tc of phospholipid membranes. The ability of the different agents to produce a new transition at a high temperature was found to correlate well with their ability to induce Friend leukemic cell differentiation. The possible mechansims of action of the chemical inducers, and the significance of the observed membrane effects on differentiation and malignancy are discussed. It is concluded that inducing agents decrease the fluidity and stabilize phospholipid membranes, and that their effects in cell differentiation might be initiated by a similar change in the properties of cell membranes.
DMSO and other cryoprotective agents produce a pronounced increase on the phase transition temperature of phospholipid membranes, indicating an increased stability. The effects of DMSO and other cryoprotective agents, divalent cations, and local anaesthetics on the transition temperature of phospholipid membranes seem to correlate with their effects on the differentiation of Friend leukaemic cells in vitro. These studies suggest that the induction of differentiation by cryoprotective agents may be the result of the interaction of these agents with cell membranes.
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Several clones of Friend leukemia cells have been established which differ in their chromosome composition. These cells also vary with regard to their responsiveness to DMSO, whereas all are responsive to butyric acid. Hence, there appears to be independent assortment of the ability of a cell line to respond to DMSO and to butyric acid, suggesting a different mechanism of action for each agent. Further, individual Friend cells possess the ability to simultaneously contain chloroacetate esterase and heme--two biochemical properties which have previously been believed to be mutually exclusive.
Studies were conducted of the in vivo therapeutic potential of compounds which induce the differentiation of Friend leukaemia cells (FLC) in vitro. DBA2/J mice were inoculated with Friend leukaemia cells grown in tissue culture and at various times thereafter were treated with either N-methylacetamide, dimethylacetamide, or tetramethylurea. While survival was only occasionally prolonged, in every study these agents significantly inhibited leukaemia cell proliferation in the spleen and to a lesser extent in the marrow. These agents had no effect on the rate of proliferation of FLC growing subcutaneously nor on the proliferation of myeloid leukaemia in RFMS mice. These studies indicate that the administration of inducing agents to mice bearing Friend leukaemia can alter the proliferation characteristics of the leukaemia cells and hence suggest that these agents may have therapeutic potential.
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The ability of families of compounds with known and potential cryoprotective properties to induce the differentiation of Friend leukemia cells in vitro was studied. For each agent, both the proportion of differentiated cells in the culture and the total amount of heme/10(7) cells were determined. Within each family of compounds there was a direct correlation between a compound's cryoprotective ability, its ability to donate electron pairs for hydrogen bonding (basicity), and its ability to induce differentiation. While individual agents differed with respect to the proportion of cells which were induced to differentiate, the biology of the process of differentiation appeared to be similar, regardless of the agent used. A cell line which was unresponsive to DMSO was responsive to other inducers, suggesting that this DMSO-resistant cell line differed from its parent DMSO-responsive cell line either in its metabolism of the inducers or in the ability of the inducers to enter the cell. Alternatively, there may be more than one mechanism involved in the chemical induction of differentiation.
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