Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Theophylline-treated cells of the human melanoma line showed an increase in NK-sensitivity in vitro and a concomitant decrease in tumorigenicity and spontaneous metastasis in Balb/c nude mice. The MeWo cells were heterogeneous and contained related subpopulations which were cloned to produce two cell lines, one hypodiploid (Cd-16) and one hypotetraploid (Ct-1). Prolonged (3 months) or short-term (4 days) treatment of these cell lines with 1 mM theophylline markedly reduced the incidence and size of tumors in Balb/c nude mice early after s.c. injection and their ability to metastasize spontaneously to the lung was also reduced. The effect was much more pronounced with Cd-16 cells, which contain amplified DNA compared to Ct-1 cells which lack DNA amplification. Part of the tumor inhibition caused by theophylline was due to natural killer (NK) cells. Thus, in vivo treatment of nude mice with anti-asialo GM1, a procedure known to remove NK cells, partially reversed the inhibitory effects of theophylline on tumor formation and generation of metastasis by Cd-16 cells. Consistent with this observation theophylline treatment enhanced the in vitro NK sensitivity of Cd-16 cells four-fold whereas Ct-1 was enhanced only slightly. The data suggest that theophylline can act preferentially on certain tumor cell subpopulations to enhance their NK-sensitive phenotype and thereby inhibit their capacity to form tumors and to metastasize in nude mice.
Clin Exp Metastasis
PMID:NK-mediated reduction of malignancy in human melanoma cells treated with theophylline. 366 24

Recombinant human interferon alpha A/D (alpha A/D) restored or augmented host defense systems against tumors in immunosuppressed mice. In normal C57BL/6 mice, inoculation of B16 melanoma F1 cells caused few pulmonary metastasis, whereas in mice pretreated with cyclophosphamide (CY) it caused a high incidence of pulmonary metastasis, leading to earlier death than in the normal mice inoculated with the same dose of the tumor. alpha A/D given after the CY treatment counteracted the deleterious effects of the CY treatment. Since such restorative activity was seen even against the subline of B16 F1 which had been made resistant to its direct antiproliferative effect, alpha A/D seems to exert its effect indirectly through host defense systems. However, this activity of alpha A/D in the mice pretreated with CY was abrogated by inoculation of anti-asialo GM1 serum but not by i-carrageenan. The CY treatment reduced NK activity, while alpha A/D given after the CY treatment restored or augmented the NK cell activity in lung cells and peripheral blood mononuclear cells, but not in spleen cells. These findings suggest that the restoration or augmentation of NK activity in the lung and/or peripheral blood might be the major factor leading to the antimetastatic activity of alpha A/D in the mice treated with CY.
Clin Exp Metastasis
PMID:Restoration by recombinant interferon alpha A/D of host defense systems against tumor in immunosuppressed mice. 369 67

Both macrophages and natural killer cells have been implicated in the antimetastatic activity of maleic anhydride-divinyl ether (MVE-5). In the present study, we attempted to utilize anti-asialo-GM1 antibody and 2-chloroadenosine, agents that kill natural killer (NK) cells and macrophages, respectively, to determine the relative contribution of each effector cell type to the overall host defense. These agents were tested in the M109 lung metastasis model in syngeneic BALB/c mice, and the cytotoxic activities of both peritoneal macrophages and splenic NK cells were followed. The most profound antitumor effect was observed when MVE-5 was given before rather than after i.v. tumor inoculation. Treatment i.p. with MVE-5 at 20 mg/kg produced greater than 98% inhibition of subsequent lung metastases when given 2 days prior to tumor. Anti-asialo-GM1 antibody (25 mg/kg, i.p.) and 2-chloroadenosine (50 mg/kg, i.p.) were administered concurrently with MVE-5. Although each agent exhibited greater selectivity for its respective target, the early (Day 2) inhibitory response was nonspecific. By Day 5 after MVE-5 treatment, 2-chloroadenosine only inhibited macrophage tumoricidal activity, and conversely, anti-asialo-GM1 antibody only inhibited NK reactivity. Despite the ability of these agents to increase survival of metastases in control animals, they only slightly abrogated the antimetastatic activity of MVE-5. Our data suggest that caution should be exercised in using these agents to discriminate macrophage and NK responses.
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PMID:Inability of anti-asialo-GM1 and 2-chloroadenosine to abrogate maleic anhydride-divinyl ether-induced resistance against experimental murine lung carcinoma metastases. 375 9

The effect of anticoagulant drugs on formation of experimental tumor metastases after i.v. inoculation of BL6 melanoma or Lewis lung carcinoma (3LL) cells was studied in mice with stimulated or depressed natural killer (NK) cell activity. When mice were treated with anticoagulants (warfarin or heparin) or when NK cell activity was stimulated by polyinosinic-polycytidylic acid, significant antimetastatic effects were observed; these effects were substantially augmented when the treatments were combined. However, when NK reactivity of mice was suppressed by anti-asialo GM1 serum or cyclophosphamide, the antimetastatic effects of warfarin and heparin were diminished or completely abrogated. In some experiments, the anticoagulants had a partial effect in mice treated with cyclophosphamide or anti-asialo GM1 serum and reduced at least to control levels the number of metastases in these mice. This limited antimetastatic effect of the anticoagulants was mostly due to the action of residual NK cells, since it was completely abrogated in mice whose NK cell activity was more completely suppressed by two injections of anti-asialo GM1 serum. In addition, the low NK reactivity of 3-week-old C57BL/6 or beige mice was sufficient to support the antimetastatic effects of the anticoagulants, effects that completely disappeared after these mice were treated with anti-asialo GM1 serum. Augmentation or abrogation of the antimetastatic effects of heparin after polyinosinic-polycytidylic acid or anti-asialo GM1 treatments, respectively, was observed in athymic nude and allogeneic BALB/c mice that received i.v. injections of B16F1 melanoma cells, indicating that the antimetastatic effects of anticoagulants depend on the presence of active NK rather than T-cells. Furthermore, adoptive transfer of NK-competent but not NK-depleted syngeneic spleen cells restored the antimetastatic effect of heparin in cyclophosphamide-treated mice. Warfarin treatment increased the elimination of radiolabeled BL6 melanoma cells from the lungs of normal mice, and the rate of tumor cell elimination was further potentiated when NK cell activity was stimulated by polyinosinic-polycytidylic acid. In contrast, after anti-asialo GM1 treatment, warfarin had no effect on the survival of i.v. administered tumor cells. Covering of YAC-1 or 3LL tumor cells with fibrin after in vitro exposure with fibrinogen and thrombin substantially protected them from the in vitro cytotoxic action of NK or lymphokine-activated killer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Augmentation of the antimetastatic effect of anticoagulant drugs by immunostimulation in mice. 380 83

The role of NK cells in the control of the metastatic spread of tumor cells was studied. Rats pretreated with rabbit anti-asialo GM1 (anti-asGM1) serum exhibited a diminished ability to destroy circulating MADB106 mammary adenocarcinoma cells, which in turn caused an increased incidence of experimental pulmonary metastasis. The anti-asGM1 treatment caused a selective inhibition of NK activity without detectable effect on T cell-mediated immunity, and overall had no effect on the cytotoxic activity or numbers of alveolar macrophages (alv.M phi) or monocytes. The suggestion of a role for NK cells in resistance to metastases from the MADB106 tumor cells was confirmed by the adoptive transfer of 5 X 10(6) highly purified large granular lymphocytes (LGL) into NK-depressed animals 2 hr before tumor challenge. This transfer of LGL, highly enriched in NK activity, partially or fully restored the ability of these rats to inhibit the development of pulmonary metastases. This ability to adoptively transfer resistance to metastases appeared to be confined to the LGL population, because transfer of the same number of mature peripheral blood T cells had no effect on tumor development. These results provide the first unequivocal evidence that LGL, with high NK activity, are involved in in vivo resistance to tumors, particularly in the elimination of potentially metastatic tumor cells from the circulation and capillary beds.
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PMID:Direct evidence for the role of LGL in the inhibition of experimental tumor metastases. 387 18

Mice treated with anti-asialo GM1 (asGM1) serum exhibited increased formation of experimental metastases in lung and liver after i.v. challenge with B16 melanoma or Lewis lung carcinoma. This increased metastasis formation coincided with decreased splenic NK activity and increased survival of i.v. injected radiolabeled tumor cells. In contrast, the injection of mice with the pyran copolymer maleic anhydride divinyl ether (MVE-2) augmented NK activity in the spleen and significantly depressed the formation of experimental metastases in the lungs and liver. However, a single or double administration of anti-asGM1 antiserum to MVE-2-pretreated mice failed to inhibit the immunoprophylaxis associated with MVE-2 administration, although it did decrease splenic NK activity and also increased the survival of i.v.-injected radiolabeled tumor cells. To address the mechanism for this dichotomy, we examined NK activity not only in the spleen but also in the blood, lungs, and livers of MVE-2-treated mice. Levels of NK activity in the lungs and liver were several-fold higher than those observed in spleen and blood. However, MVE-2-augmented NK activity in lung and liver was more resistant to depletion by the standard regimen of anti-asGM1 treatment than was NK activity in blood and spleen, and required two high-dose administrations of a higher titered antiserum for depletion of the augmented response. This high-dose regimen removed all detectable NK activity from the lung and liver, and concomitantly eliminated the metastasis-inhibiting effect of MVE-2. These data are consistent with a role for organ-associated NK cells in inhibiting metastasis formation during the extravasation and/or early postextravasation phases of the metastatic process. The results also suggest that biologic effects of NK activity in spleen and blood can be dissociated from those mediated by NK activity in other organs by use of different treatment regimens with anti-asGM1 serum. Finally, because NK activity in target organs can be augmented to an even greater extent than in the blood and spleen by at least some biologic response modifiers (BRMs), organ-associated NK activity should be considered as a possible mechanism for the therapeutic effects of BRM treatment.
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PMID:Role of organ-associated NK cells in decreased formation of experimental metastases in lung and liver. 398 7

Liposomes incorporating a variety of immunomodulators have been shown to activate macrophages and monocytes for tumoricidal activity both in vivo and in vitro. We report that in addition to the activation of macrophages, the i.v. injection of liposomes (multilamellar vesicles) that have encapsulated muramyl tripeptide-phosphatidylethanolamine (MTP-PE) could also augment interstitial natural killer (NK) cell activity in the lung and the liver. In contrast, liposomes incorporating MTP-PE were unable to augment NK cell activity in the spleen, peripheral blood, or peritoneal cavity (after i.p. injection). In addition, liposomes did not augment splenic NK cell activity in vitro. This suggests that the augmentation of NK cell activity in the lungs and liver was not due to direct effects of the liposomes but may have been a secondary effect mediated by a monokine. The augmentation of pulmonary NK cell activity was paralleled by the nonspecific immunoprophylaxis of experimental pulmonary metastases. The augmented NK cell activity, as well as the enhanced nonspecific immunoprophylactic activity, was reduced by pretreatment of the mice with anti-asialo GM1 antiserum. Thus, the augmentation of organ-associated NK cell activity by liposomes incorporating MTP/PE plays a major role in the host's increased resistance to the formation of experimental metastases.
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PMID:Augmentation of NK cell activity in tissue specific sites by liposomes incorporating MTP-PE. 400 28

The effect of thioglycollate-elicited macrophages (TG-M phi) on natural killer (NK)-cell activity and metastases formation in mice was investigated. Intravenously (i.v.) inoculated TG-M phi inhibited spleen NK activity of normal mice and abrogated polyinosinic: polycytidylic (poly I:C) induced augmentation of NK cell function. TG-M phi also inhibited the clearance of i.v.-injected radiolabeled B16 melanoma cells from the lungs of normal or poly I:C stimulated mice. Formation of experimental B16 melanoma metastases was dramatically increased in mice pretreated with TG-M phi. Administration of TG-M phi increased metastasis formation to a greater extent than anti-asialo GM1 serum, while anti-asGM1 serum was more efficient than TG-M phi in depressing spleen NK cell activity. When mice with low NK reactivity (beige mice or mice treated with anti-asialo GM1 serum) were inoculated with TG-M phi, there was a substantial additive augmenting effect on metastasis formation in the lungs. Treatment with poly I:C elevated NK-cell activity and had profound antimetastatic effects in normal but not in TG-M phi pretreated mice. The metastasis augmenting effect of TG-M phi was fully expressed in poly I:C-treated mice as well as in athymic nude mice. Inoculation of proteose peptone-elicited macrophages (PM phi), unlike TG-M phi, did not depress NK activity or augment metastasis formation in normal or poly I:C-treated mice. However, since the inhibition of NK activity in TG-M phi-treated mice was relatively weak, and a substantial additional increase in metastases was observed in NK-depressed mice after transfusion of TG-M phi, it seems unlikely that the TG-M phi-induced inhibition of NK reactivity is entirely responsible for the augmented formation of metastases. Further studies revealed that i.v. inoculation of TG-M phi, but not PM phi, induced intravascular inflammatory reactions, and damage to endothelial cells and basement membrane of the lung vasculature. These reactions may contribute to increased tumor cell extravasation and metastasis formation in mice pretreated with TG-M phi.
Clin Exp Metastasis
PMID:Influence of adoptively transferred thioglycollate-elicited peritoneal macrophages on metastasis formation in mice with depressed or stimulated NK activity. 404 60

We have studied the role of natural killer activity during the growth and dissemination of a transplantable renal adenocarcinoma (Renca) of spontaneous origin in BALB/c mice. The pattern of growth of this tumor accurately mimics that of adult human renal cell carcinoma in terms of clinical stages I-IV, particularly with regard to spontaneous metastasis to lung and liver. Renca is moderately sensitive to lysis by natural killer cells from normal mice and is more efficiently lysed by natural killer cells from mice treated with the biological response modifier maleic anhydride divinyl ether, a pyran copolymer. Our studies demonstrate that selective depression of natural killer activity by administration of antiserum specific for the neutral glycosphingolipid asialo GM1 correlated with increased formation of spontaneous metastases in the lungs, liver, and lymph nodes. Conversely, augmentation of natural killer activity by the biological response modifier decreased the formation of spontaneous metastases in lungs, liver and lymph nodes. Further, the suppression of natural killer activity and subsequent increased formation of metastases were accompanied by a significantly reduced survival time, whereas the augmented natural killer activity and decreased incidence of metastases in biological response modifier-treated mice were accompanied by an increase in time of survival. These results demonstrate a significant role for natural killer cells in the control of spontaneous metastasis during growth of this murine renal cancer.
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PMID:Role of natural killer activity in development of spontaneous metastases in murine renal cancer. 405 25

Natural killer (NK) activity in the rat and human has been attributed to cells having the morphology of large granular lymphocytes (LGL). However, this association has been less clear in the mouse, largely because of difficulties in obtaining highly enriched populations of LGL from normal spleen and blood. We have previously observed that the administration of the biological response modifier (BRM) maleic anhydride divinyl ether (MVE-2) strongly augmented NK activity in lung and liver, and the augmented NK activity coincided with increased resistance to the formation of experimental metastases in these organs. The degree of NK augmentation was most striking in the liver, an unexpected and previously unreported observation. In the present study, both MVE-2 or Corynebacterium parvum induced a dramatic augmentation of liver NK activity, which reached maximum levels 3-5 d after treatment. This augmentation of NK activity in the liver coincided with a large increase in the number of lymphoid cells with the morphological characteristics of LGL that could be isolated from enzymatically digested suspensions of perfused liver. The yield of LGL per liver following BRM treatment corresponded to a 10-50-fold increase as compared to normal mice. LGL were purified from these enzymatically digested suspensions of perfused liver by depletion of adherent cells on nylon wool columns and subsequent enrichment for low-density lymphoid cells by fractionation on Percoll density gradients. The enrichment of LGL correlated with greatly increased NK activity against YAC-1. Conversely, the higher-density fractions were depleted of both LGL and NK activity. This increase in NK activity in the liver was suppressed by in vivo treatment with anti-asialo GM1 (asGM1) serum. This treatment also resulted in a corresponding reduction in both the total number and percentage of LGL. By flow cytometry analysis, the phenotype of the majority of these highly cytolytic LGL isolated from the livers of BRM-treated mice were asGM1+, Thy-1+, Ly-5+, Qa-5+, Mac-1+, and Gma-1+, whereas these LGL were Ly-1-, Lyt-2-, L3T4-, and surface Ig-. We conclude that the livers of BRM-treated mice can provide a rich source of highly active mouse LGL that could be used for further characterization of this lymphocyte subset. Further, these studies imply a potential for BRM therapy of neoplastic or viral diseases through augmentation of organ-associated immune responses.
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PMID:Augmentation of organ-associated natural killer activity by biological response modifiers. Isolation and characterization of large granular lymphocytes from the liver. 649 1


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