摘要:

AbstractWe have previously demonstrated that the chlorphentermine (CP)1-induced impairment in lymphocyte blastogenesis involves drug-induced inhibition of an event which occurs very early during lymphocyte activation. An early event, which is associated with mitogen-induced lymphocyte activation, involves the hydrolysis of phosphatidylinositol by phospholipase C to yield inositol phosphates and diacylglycerol as products. Inositol phosphates and diacylglycerol then function as mediators of a trans-membrane signal for the continuation of the cellular response. It was the purpose of the present study to determine the effects of CP on this phosphatidylinositol pathway. We demonstrated that formation of inositol phosphates in lymphocytes increases progressively above control over a 2 hour period following concanavalin A (Con A)-stimulation. In contrast, lymphocytes pre-incubated with 10−5M CP for 60 min, then stimulated with Con A for 2 hours in the presence of 10−5M CP, exhibit a significantly depressed inositol phosphate formation. In addition, CP also inhibited the activity of phospholipase C (IC50= 0.58 mM), the enzyme responsible for the formation of inositol phosphates during lymphocyte activation. Further, lymphocytes activated in a manner that bypasses the phosphatidylinositol pathway are not inhibited by 10−7M or 10−9M CP as are cells activated with Con A. These results suggest that the suppression of the phosphatidylinositol pathway may be involved in the inhibition by CP of lymphocyte blastogenesis induced by Con A.

ISSN:0892-3973    

DOI:10.3109/08923978809014398

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

AbstractA variety of cyclooxygenase (FCO) and 5-lipoxygenase (5-LPO) inhibitors were tested for their ability to modulate murine thymocyte proliferation induced by IL-1 and suboptimal levels of the mitogen phytohemagglutinin (PHA). The contribution of drug toxicity to inhibition of3H-thymidine incorporation was estimated by measuring MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) formazan production in the thymocyte cultures at the end of the assay. Cyclosporin A and dexamethasone, two positive control compounds, potently inhibited thymocyte proliferation at extremely low concentrations (0.01 and 0.001μg/ml respectively), although activity roughly paralleled toxicity. In contrast, 5-LPO inhibitors (AA-861, BW-755c, and ETYA), but not selective FCO inhibitors (ibuprofen and indomethacin), suppressed lymphoproliferation at nontoxic concentrations, suggesting that products of the 5-LPO pathway may mediate the thymocyte proliferative response induced by IL-l/PHA. Attempts to counteract the suppressive activity of 5-LPO inhibitors by addition of leukotriene (LT) B4, LTC4, LTE4, 5-HETE, and 15-HETE were unsuccessful.

ISSN:0892-3973    

DOI:10.3109/08923978809014399

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

AbstractThe role of arachidonic acid metabolites as second messengers in the IL-3-induced activation of DA-1 cells was examined. By using inhibitors of either the cyclooxygenase (CO) or lipoxygenase (LPO) pathways, we determined that neither prostaglandins nor leukotrienes were involved in signal transduction, since aspirin, indomethacin, meclofenamic acid, and nordihydroguaiaretic acid (NDGA) failed to inhibit the proliferation response of DA-1 cells to IL-3. Furthermore, two combination CO/LPO inhibitors, benoxaprofen and BW755c, failed to inhibit DA-1 proliferation. A new CO/LPO compound examined, SK&F 86002, did inhibit proliferation (IC50= 30μM±14, N=11), leading us to conclude this drug has other actions besides CO/LPO inhibition. Finally, direct measurement of3H-arachidonic acid uptake by DA-1 cells failed to show a difference in the amount of3H-arachidonic acid incorporated in the presence of limiting or saturating amounts of IL-3. We conclude from these data that arachidonic acid metabolites are not involved in transmembrane signalling by IL-3 in DA-1 cells.

ISSN:0892-3973    

DOI:10.3109/08923978809014400

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

AbstractThe therapeutic effect of OK-432 induced endogenous TNF on tumor bearing mice and cancer patients was investigated.OK-432 (10 KE/mouse) was administered intraperitoneally to Balb/c mice 7 days prior to the transplantation of Meth A cells (1×106/mouse) into the abdominal cavity. And at day 1 of tumor inoculation, 1 KE/mouse of OK-432 was administered intraperitoneally.The significant prolongation of life span was observed in these mice.On the basis of these observation, therapeutic effect of endogenous TNF on cancer patients was clinically evaluated. OK-432 was administered intraperitoneally or intrapleurally to cancer patients with peritonitis carcinomatosa or pleuritis carcinomatosa 4 times (10KE each) every other day and 50KE of OK-432 was readministered with the interval of 7 days.An appreciable activity of TNF was detected in peritoneal fluids or pleural effusion, and the significant decreasing of these fluids was observed. It is therefore concluded that these therapeutic approach may well be taken into account in treatment of cancer.

ISSN:0892-3973    

DOI:10.3109/08923978809014401

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

AbstractThe response of a highly metastatic cell line of methylcholanthrene induced A fibrosarcoma (Meth A) to growth factors from platelets was examined. The highly metastatic cell subline (MH) proliferated more rapidly than its parental counterpart cell subline (ML) in a medium containing platelet lysate. However, when the three major growth factors from platelets, ie, platelet-derived growth factor, epidermal growth factor, and transforming growth factor-β(PDGF, EGF, TGF-β), were independently examined for their growth promoting activity, the former 2 growth factors preferentially stimulated the proliferation of ML and the latter growth factor rather suppressed the growth of both cells.On the other hand, the combined effects of these factors were more marked on MH. This combination effect was supported by the evidence that the number of receptors for EGF (which is probably an essential growth factor for the Meth A cell) was increased by pretreatmenl with PDGF or TGF-β. Thus, the highly metastatic cells of MH were considered to be the most susceptible to growth factors released from platelets. This conclusion is consistent with the concept that platelets may play an important role in the formation of blood-borne metastasis by releasing growth factors to promote the proliferation of tumor cells, following aggregation with tumor cells.

ISSN:0892-3973    

DOI:10.3109/08923978809014402

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

AbstractThein vivoandin vitroinfluence of lithium lactate on mouse natural killer activity was investigated.In vitroexposure of effector-target mixture to graded concentrations of lithium did not substantially modify the natural killer activity of mouse splenocytes, untreated or pretreated with cyclophosphamide. Howeverin vitrotreatment of effector splenocytes increased the frequency of NK-percursor cells.Thein vivotreatment with lithium lactate greatly increased the natural killer activity in intact mice, whereas it did not improve this cytotoxic function in host immunodepressed by cyclophosphamide.These data suggest that lithium salts produce a modulation of natural killer activity of mouse spleen cells, probably through a mechanism involving the increase of the number of NK-precursors in hosts not subjected to cytotoxic chemotherapy.

ISSN:0892-3973    

DOI:10.3109/08923978809014403

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

AbstractThe effect that MnCl2has on murine splenic natural killer (NK) cell activity was investigated in infant (10 days old), pre-weanling (18 days old) and weanling (24 days old) C57BL/6J mice. A single intraperitoneal injection of 10, 20 or 40μg MnCl2/g body weight caused a significant enhancement in NK activity, as determined by the in vitro51Cr release assay. Comparable enhancement of NK activity was observed for age-matched mice injected intraperitoneally with polyinosinic polycytidylic acid (Poly I:C). Both MnCl2and Poly I:C caused elevations in serum interferon levels. Time-course studies revealed that interferon levels returned to normal within 48 hours following injection with either MnCl2or Poly I:C; however enhanced NK activity persisted for up to 48 hours in Poly I:C-injected mice and 72 hours in MnCl2-injected mice. The administration of rabbit anti-asialo GMl to MnCl2-injected mice completely abrogated the enhanced NK activity. In addition, the injection of rabbit anti-mouse interferon a,α,βbut notγcompletely abrogated the enhancement of NK activity by MnCl2and to a lesser extent the enhancement of NK activity by Poly I:C. These results indicate that despite low levels of NK activity in pre-weanling mice, MnCl2is capable of enhancing this activity by 8–9 fold. Furthermore, Mn-enhanced NK activity in these young mice appears to be mediated by the production of interferonα,β.

ISSN:0892-3973    

DOI:10.3109/08923978809014404

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

AbstractThe participation of lysosomal enzymes, hydroxyl radicals, and mitochondrial respiration in the cytocidal effect of TNF on tumor cells was investigated.The cytotoxicity of TNF on L-M cells was clearly reduced by lysosomotropic agents, DMSO (hydroxyl radical scavenger), NDGA (lipoxygenase inhibitor), and sodium azide (mitochondrial respiration inhibitor).The results suggest that lysosomal enzyme and hydroxyl radicals play an important triggering role in the destruction of tumor cells by TNF, and that the process of destruction might require ATP.

ISSN:0892-3973    

DOI:10.3109/08923978809014405

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

AbstractA synergistic increase in the cytotoxic effects of recombinant human tumor necrosis factor (rH-TNF) and anti-cancer drugs was demonstrated in vitro. The cytotoxicity of rH-TNF against L-M cells in combination with Mitomycin C (MMC), Adriamycin (ADM), Cytosine arabinoside (Ara-C), Actinomycin D (ACD), Daunomycin (DM), Cisplatin (CDDP), Vincristin (VCR), and 5-Fluorouracil (5FU), based on the concentration necessary for 50% inhibition of cell growth (IC50), was 4 to 347 times as high as that of rH-TNF alone. The results suggest that combination therapy including rH-TNF and anti-cancer drugs may be of value in the treatment of malignancy in human patients.

ISSN:0892-3973    

DOI:10.3109/08923978809014406

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor