calcimycin and Lymphoma--Non-Hodgkin

Bleomycin and asparaginase are widely used antineoplastic agents which may induce allergic or inflammatory side-effects. Mast cells are implicated as effector cells in allergic and inflammatory responses. The aim of this study was to establish whether bleomycin or asparaginase modulate leukotriene production in vitro and in vivo. Leukotriene C4 (LTC4) production by murine bone marrow-derived mast cells (BMMC) was determined by radioimmunoassay (RIA). Leukotriene production in patients was assessed by determining leukotriene E4 and N-acetyl-leukotriene E4 in urine by means of combined HPLC and RIA. Bleomycin induced an up to 2.1-fold increase in LTC4 production both in unstimulated and in calcium ionophore-stimulated mast cells. In 3 of 7 patients treated with bleomycin, a greater than 2-fold increase in endogenous leukotriene production was observed. This effect was associated with febrile responses and was most pronounced in a patient who developed an Adult Respiratory Distress Syndrome (ARDS). Asparaginase increased leukotriene production up to 10-fold in stimulated but not in unstimulated BMMC. In a patient who developed an anaphylactic reaction after treatment with asparaginase, a pronounced increase in urinary leukotriene concentration was observed. In contrast to bleomycin or asparaginase, a number of other cytostatic agents did not significantly change leukotriene production by BMMC. Our data indicate that some of the inflammatory and allergic side-effects of bleomycin and asparaginase could be mediated by leukotrienes, a possible source of which may be mast cells.

Topics: Adult; Anaphylaxis; Animals; Antineoplastic Agents; Asparaginase; Bleomycin; Calcimycin; Drug Hypersensitivity; Humans; In Vitro Techniques; Inflammation; Ionophores; Leukotriene C4; Leukotriene E4; Leukotrienes; Lymphoma, Non-Hodgkin; Mast Cells; Mice; Mice, Inbred BALB C; Respiratory Distress Syndrome

The activation marker CD30 is expressed on the cell surface of the malignant cells in Hodgkin's disease and a few non-Hodgkin lymphomas. We have analyzed the regulation of membrane-bound CD30 and found that the binding of a variety of anti-CD30 antibodies induced down-regulation of CD30 on cell lines. In addition, such down-modulation was also observed after treatment of the cell surface proteins with the sulfhydryl reagent iodoacetamide or after stimulation of the second messenger pathway with phorbol ester or calcium ionophore. This modulation was abolished at 4 degrees C and strongly inhibited by chelators like EDTA or 1,10-phenanthroline, whereas EGTA, a selective inhibitor of Ca(2+)-dependent proteinases and other inhibitors of serine, thiol and acid proteinases, showed no effect. The down-modulation was strengthened by Zn2+ or Cd2+, but not by other divalent cations such as Fe2+, Mn2+, Mg2+, Ca2+ or Co2+, thus indicating the involvement of a zinc metalloproteinase in CD30 modulation which can be activated by protein kinase C and by alkylation of sulfhydryl groups. Pulse-chase experiments, analysis of the CD30 glycosylation and specific measurement of the 90-kDa soluble form of CD30 (sCD30) with a sandwich radioimmunoassay revealed that CD30 down-modulation results from enhanced release of 90-kDa sCD30 by the site-specific cleavage of CD30 accomplished by a zinc metalloproteinase. This release occurs at the cell membrane without prior endocytosis.

Topics: Antibodies, Monoclonal; Calcimycin; Down-Regulation; Glycosylation; Hodgkin Disease; Humans; Iodoacetamide; Ionophores; Ki-1 Antigen; Kinetics; Lymphoma, Non-Hodgkin; Metalloendopeptidases; Solubility; Sulfhydryl Reagents; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Mechanisms of adhesion between tumor cells and hepatocytes, which are likely to play a role in liver metastasis formation, were studied in vitro. TA3 mammary carcinoma and MB6A lymphosarcoma cells were added to rat hepatocytes that had been cultured for 24 hours. Adhesion was quantified by counting adherent cells seen in sections of pelleted, Epon-embedded culture fragments. Adhesion of TA3, but not of MB6A cells, was inhibited by antibodies prepared from an antiserum raised against sinusoidal face-enriched liver plasma membranes. Detergent-solubilized liver components, affinity purified on immobilized inhibitory antibodies, neutralized inhibition, whereas a subfraction separated from this material with the use of immobilized noninhibitory antiliver antibodies had no neutralizing activity. Adhesion of MB6A but not of TA3 cells was inhibited by the calcium ionophore A23187 and the local anesthetic procaine. The calmodulin inhibitor trifluoperazine inhibited adhesion of MB6A cells more strongly than that of TA3 cells. Finally, adhesion of TA3 cells was dependent on external calcium, whereas in the case of MB6A cells calcium could be replaced by magnesium. These observations suggested that adhesion of the two tumor cell types to hepatocytes involved distinct hepatocyte surface molecules and required distinct biochemical machinery.

Topics: Animals; Antigens, Surface; Calcimycin; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cells, Cultured; Female; Liver; Lymphoma, Non-Hodgkin; Mammary Neoplasms, Experimental; Molecular Weight; Procaine; Rats; Trifluoperazine

Concentrations of the divalent cation ionophore, A23187, optimal for the transformation of human and pig lymphocytes, were cytotoxic to lymphocytes from rats and mice. The biochemical effects associated with A23187-induced cytolysis in rat thymocytes included inhibition of [3H]uridine uptake and incorporation into macromolecules and stimulation of [14C]-alpha-aminoisobutyric acid uptake. The biochemical effects, as well as the reduction in the number of viable cells, were dose dependent and were blocked by the omission of ionic calcium from the incubation medium. At a given ionophore concentration, the magnitude of lysis of thymocytes was proportional to the concentration of Ca2+ in the extracellular medium. Sr2+ was less effective than was Ca2+ in supporting A23187-induced thymocyte lysis. A comparison of the lytic response of lymphocytes of various origins showed that extracellular Ca2+ plays a role in ionophore-induced cytolysis in thymocytes and lymph node lymphocytes but not in mouse lymphosarcoma P1798 cells.

Topics: Aminoisobutyric Acids; Animals; Anti-Bacterial Agents; Calcimycin; Calcium; Cell Survival; Female; In Vitro Techniques; Lymphocytes; Lymphoma, Non-Hodgkin; Magnesium; Male; Mice; Mice, Inbred BALB C; Rats; Sarcoma, Experimental; Strontium; T-Lymphocytes; Uridine