Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149925 (small cell lung cancer)
 6,491 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction between LFA-1 and its natural ligand, ICAM-1, plays an important role in leukocyte adhesion and signal transduction. LFA-1-mediated T-cell adhesion is generally activated by CD3-mediated signal in association with T-cell receptor-mediated recognition of the antigen/major histocompatibility complex on antigen-presenting cells. In the present study, we compared spontaneous or bispecific antibody (BsAb)-directed LAK cell cytotoxicity against ICAM-1+ or ICAM-1- small cell lung cancer (SCLC) cell lines. gamma-Interferon (IFN-gamma)-induced ICAM-1 expression on ICAM-1- SCLC cell lines, and susceptibility to LAK cells was increased simultaneously. Increased cytolysis of the IFN-gamma-treated SCLC was inhibited by an anti-ICAM-1 monoclonal antibody (mAb). Furthermore, LAK cell cytotoxicity directed by BsAb, which was composed of OKT3 and anti-SCLC mAb, was also increased by the IFN-gamma treatment of SCLC, and this increase was inhibited by an anti-ICAM-1 mAb but not by anti-Class I or anti-CD2 mAb. These results suggest that a prior administration of IFN-gamma would enhance the efficacy of the following specific targeting therapy utilizing BsAb and LAK cells by up-regulating the ICAM-1 expression on tumor target cells. The combinational use of IFN-gamma and anti-CD3 x anti-tumor BsAb might be a promising way of enhancing LAK cell-mediated adoptive immunotherapy in small cell lung cancer patients.
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PMID:Induction of intercellular adhesion molecule 1 on small cell lung carcinoma cell lines by gamma-interferon enhances spontaneous and bispecific anti-CD3 x antitumor antibody-directed lymphokine activated killer cell cytotoxicity. 138 Dec 73

The response of class I major histocompatibility complex antigen expression to in vitro administration of interferon and tumor necrosis factor alpha (TNF-alpha) was measured using class I major histocompatibility complex-deficient small cell lung cancer cell lines. Significant induction also was observed using gamma interferon (IFN-gamma) alone, whereas TNF-alpha alone yielded only modest induction. Classic small cell lung cancer cell lines NCI-H146 and NCI-H209 best demonstrated synergistic HLA and beta 2-microglobulin antigen induction with IFN-gamma and TNF-alpha with the following dose schedule: 3-6 days of TNF-alpha (200 units/ml) followed by 48 h of IFN-gamma (100 IU/ml). Induction was quantitated using an 125I-Protein A radioimmunoassay. Synergistic induction of the HLA and beta 2-microglobulin surface antigens on NCI-H146 was also possible with alpha interferon and TNF-alpha but required a higher concentration of the interferon, i.e., 3-6 days of TNF-alpha (200 units/ml) followed by 48 h of alpha interferon (1000 units/ml). Small cell lung cancer cell line NCI-H146 was further studied for expression of major histocompatibility complex messenger RNA using the optimal doses and sequence of addition of IFN-gamma and TNF-alpha as indicated above. A significant induction with IFN-gamma alone and synergistic induction with both IFN-gamma and TNF-alpha was quantitated for both HLA-A2 and beta 2-microglobulin transcripts using Northern blot analysis. Incubation with relatively low subcytotoxic doses of IFN-gamma and TNF-alpha also resulted in a marked synergistic decrease in c-myc message.
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PMID:Potentiation of interferon induction of class I major histocompatibility complex antigen expression by human tumor necrosis factor in small cell lung cancer cell lines. 255 49

The colony-inhibitory effects of recombinant human tumor necrosis factor (rH-TNF) and recombinant human interferon-gamma (rH-IFN-gamma) were evaluated in four human lung cancer cell lines and their cisplatin-resistant sublines. The cell lines tested were PC-7 and PC-9 (adenocarcinoma), H69 and N231 (small cell lung cancer) and four cisplatin-resistant sublines, PC-7/1.0, PC-9/0.5, H69/0.2 and N231/0.2, which were 20.0, 7.1, 4.8 and 8.4 fold resistant to cisplatin, respectively, compared to the respective parental cell line in terms of IC50 in a soft agar colony assay. All parental cell lines were resistant to rH-TNF and rH-IFN-gamma, alone or in combination. However, two resistant sublines showed sensitivity to rH-TNF and rH-IFN-gamma. Colony formation by PC-9/0.5 was significantly inhibited, in the absence or presence of cisplatin, by 10(2) U/ml of rH-TNF (less than 50% of control) and the inhibition was synergistic with that produced by 10(3) or 10(4) U/ml of rH-IFN-gamma. RH-IFN-gamma inhibited the colony formation of H69/0.2 only at the highest concentration tested (10(4) U/ml) (less than 50% of control) and the combined effect with rH-TNF was additive. These results suggest that rH-TNF and rH-IFN-gamma may have some potential in overcoming cisplatin resistance by virtue of collateral sensitivity.
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PMID:In vitro growth inhibition of cisplatin-resistant human lung cancer cell lines by recombinant human tumor necrosis factor and/or recombinant human interferon-gamma by virtue of collateral sensitivity. 312 62

Recent evidence suggests that deficient HLA Class I expression in SCLC lines may be due, in part, to down-regulation of TAP-1 and TAP-2 expression, and, thus, deficient antigen processing. Given the capability of the multidrug transporter mediating MDR, P-gp, to transport peptides, we hypothesized that P-gp may substitute for TAP-1/TAP-2 and enhance antigen processing in SCLC. To investigate this, we studied the H69 line (parent SCLC) and VPR-2 (MDR subline selected in etoposide, P-gp +). HLA-A,B,C expression was significantly increased in VPR-2 cells relative to H69, and was much more inducible with IFN-gamma. TAP-1 and TAP-2 were expressed at low levels in both lines. Differential induction of TAP-1 expression with IFN-gamma exposure was observed, with a dramatic increase in VPR-2 cells, and no change in H69. TAP-2 expression was enhanced in both lines with IFN-gamma, but to a greater degree in VPR-2. VPR-2 cells were resistant to LAK killing relative to H69, and were minimally sensitized with IFN-gamma. In contrast, IFN-gamma enhanced susceptibility of H69 to LAK killing 3-fold. The direct correlation between enhancement of HLA-A,B,C expression by IFN-gamma and the differential inducibility of TAP-1 and TAP-2 expression in P-gp-SCLC lines is novel. Relative LAK sensitivity of H69 and its increase by IFN-gamma may have clinical implications.
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PMID:Enhanced expression of HLA-A,B,C and inducibility of TAP-1, TAP-2, and HLA-A,B,C by interferon-gamma in a multidrug-resistant small cell lung cancer line. 806 Nov 13

Thirteen human lung cancer cell lines, 7 representing small cell lung cancer (SCLC) and 6 different types of non-SCLC, were tested for sensitivity to tumour necrosis factor alpha (TNF-alpha) and interferon alpha and gamma (IFN-alpha and gamma) using an automated fluorometric microculture cytotoxicity assay (FMCA). One SCLC line (H-82) was found to be sensitive to IFN-alpha in short-term (72 h) culture, whereas after prolonged (5 days) culture two additional SCLC cell lines responded to IFN-gamma. TNF-alpha inhibited the growth of one large cell carcinoma cell line (H-157), whereas all SCLC lines were found to be insensitive. The combination of IFN-gamma and TNF-alpha produced no further response compared with the single agents used alone. By continuous cultivation of the IFN-alpha-sensitive cell line H-82 in the presence of increasing concentrations of IFN-alpha, an IFN-alpha-resistant subline (H-82) was established. This line displayed a high degree of resistance ( > 100 fold) to IFN-alpha and cross-resistance to IFN-gamma. There was no alteration in the number of IFN binding sites, in the growth rate, the expression of selected surface markers for SCLC or the expression of multidrug resistance markers in the H-82R subline compared with the parental H-82 cell line. The results demonstrate a heterogeneous response of SCLC cell lines to IFN-alpha and gamma and TNF-alpha with only a minority of the cell lines responding to these agents by growth inhibition. The IFN-alpha and gamma H-82R subline may serve as a valuable tool in future studies on the mechanisms of IFN antitumour activity.
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PMID:Effects of interferons and tumour necrosis factor-alpha on human lung cancer cell lines and the development of an interferon-resistant lung cancer cell line. 869 64

Interleukin (IL)-15 is a novel cytokine with IL-2-like activity. In the present study, we examined IL-15-mediated induction of killer activity of peripheral blood mononuclear cells (MNC) against lung cancer cell lines, and the regulatory mechanisms of this induction by IL-15. Cytotoxic activity was measured by 51Cr release assay. IL-15 at concentrations of more than 10 ng/ml induced significant killer activity of blood MNC against a small cell lung cancer cell line (SBC-3), as well as Daudi cells, and 50 ng/ml was considered its optimal concentration. A time course study revealed that an incubation period of 4-6 days was optimal for induction of killer activity. MNC cultured with IL-15 also exhibited killer activity against other lung cancer cell lines (H-69, N-291 and PC-9 cells). IL-15 and IL-12 had additive effects on induction of killer activity against SBC-3 cells. On the other hand, IL-15 had no synergistic or additive effect on induction of killer activity by IL-2. Fresh human monocytes isolated by centrifugal elutriation augmented the development of killer activity of lymphocytes stimulated by IL-15. As a humoral regulatory factor, IL-4 had a suppressive effect on induction of killer activity by IL-15. IFN-gamma, IL-1beta, TNF-alpha, IL-6 or IL-10 had no effect on induction of killer activity by IL-15 at the optimal concentration. These results suggest that IL-15 has potential for the immunotherapy of lung cancers.
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PMID:Induction by interleukin-15 of human killer cell activity against lung cancer cell lines and its regulatory mechanisms. 904 60

We have found that many synthetic selenoorganic compounds, including ebselen, have immunotropic activity. These studies were designed to assess the effect of the analog of ebselen bis[2-pyridyl (2-carbamoyl) phenyl]diselenide (AE-22) on human leukocytes that may express various activation states. The cells were obtained from bronchoalveolar lavage (BAL) cells of patients with various inflammatory lung diseases. The AE-22-treated BAL cells from patients with bronchial asthma (n = 6) and with small cell lung cancer (SCLC) (n = 6) were compared with these in the peripheral blood leukocytes (PBL) from the same donors. The control group comprised 5 patients who underwent diagnostic examination and were free of any cancer or concomitant diseases. Secretion of TNF-alpha, IL-6, and IFN-gamma was considered as a marker of BAL or PBL cell activation. Different response of the cells and various effects of AE-22 were observed in relation to the origin and functional state of leukocytes. It was established that AE-22 can induce TNF-alpha, IL-6, and IFN-gamma in a dose-dependent manner in BAL cells and PBL isolated from healthy individuals. However, BAL cells were found to be less reactive than PBL as cytokine producers. In contrast, AE-22 had no effect on BAL cells obtained from patients with lung cancer, which were found to be hyporeactive to phytohemagglutinin and bacterial lipopolysaccharide and did not produce TNF-alpha, IL-6, or IFN spontaneously. The spontaneous release of cytokines by BAL cells from bronchial asthma patients, but not by PBL from the same individuals, was significantly (p < 0.01) higher than that from the cultures of healthy control subjects. The high secretion of cytokines by the locally activated BAL cells was significantly (p < 0.01) reduced after administration of AE-22. The results suggest that AE-22 has immunomodulatory activity. AE-22 can downregulate the hyporeactive BAL cells from asthmatics, but it appears to be inactive in BAL cells of cancer patients who can tolerate the cytokine inducers.
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PMID:Modulation of cytokine production by a selenoorganic compound (AE-22) in hyperreactive or hyporeactive bronchoalveolar leukocytes of asthmatics or lung cancer patients. 935 62

In this study, we have analyzed the possibility of inducing T cell responses against small cell lung cancer (SCLC), a still incurable tumor, by cytokine gene transfer approaches. By RT-PCR analysis most SCLC expressed the CTL-defined tumor antigens MAGE-3 (10/11), MAGE-1 (7/11) and less frequently BAGE (4/11) and GAGE1,2 (4/11). Although the surface expression of HLA class I molecules was low on most SCLC, thus preventing CTL recognition, treatment of the cells with IFN-gamma enhanced HLA-class I levels in all cases. Two MAGE3+ SCLC cell lines displaying the A2 HLA-class I allele, involved in MAGE-3 antigen presentation to CTL, were stably transfected with the IFN-gamma gene (alone or co-transfected with IL-2). IFN-gamma-transfected cells displayed a clearcut increase in expression of HLA-class I and beta 2-microglobulin at both protein and mRNA level, and of TAP-1 and TAP-2 mRNA. Perhaps more importantly, IFN-gamma transfected cells were recognized by the MAGE-3-specific A2-restricted antimelanoma CTL clone 297/22, while unmodified cells or cells transfected with the IL-2 gene alone were not. These data indicate that IFN-gamma gene transfection into HLA-deficient SCLC cells is able to restore their ability to present endogenous tumor antigens to CTL and that IFN-gamma gene transfer approaches may be attempted to induce specific CTL responses in SCLC.
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PMID:IFN-gamma gene transfer restores HLA-class I expression and MAGE-3 antigen presentation to CTL in HLA-deficient small cell lung cancer. 941 8

The relationship and in situ interactions between interleukin 2 (IL-2)-regulated mediators remain unclear, particularly in lung cancer model. The purpose of the present study was to determine in vitro effect of IL-2 on the secretory activity of bronchoalveolar leukocytes from 11 patients with previously untreated small cell lung cancer (SCLC) and 9 patients with non-small cell lung cancer (NSCLC). Control group (n = 6) comprised patients who underwent diagnostic investigations and were free of any clinical or radiographic evidence of lung diseases. IL-2-induced secretion of mediators was compared with that following stimulation with lipopolisaccharide (LPS; 5 micrograms/ml) or Newcastle disease virus (NDV; 640 HU/ml). Obtained from bronchoalveolar lavages (BAL) cells were cultured for 24-48 h in the presence or absence of inducers. The levels of cytokines were determined in BAL cell supernatants by bioassays. Nitric oxide (NO) was estimated by colorimetric method in Griess reaction. Compared with normal controls, the spontaneous secretion of the above mediators excluding IFN-gamma in BAL cultures from NSCLC group was elevated by up to 20-30-fold and further increase was observed after stimulation with LPS. However, very low secretion of cytokines and NO was found in BAL leukocyte cultures activated by IL-2. In contrast, the cells obtained from SCLC group produced little detectable levels of TNF-alpha (median 12.0, range 3-45 U/ml), IFN-gamma (median 3, range 3-12 U/ml) and IL-6 (median 15, range 6-45 U/ml) in response to LPS and interferons, mainly IFN-alpha; (median 3, range 3-12 U/ml) in response to NDV. Although, upon IL-2-stimulation was observed only noteworthy production of IL-6 (median 405, range 45-1215 U/ml). IL-2-induced secretion of IL-6 was accompanied by up to 5-fold augmented secretion of NO in comparison with NSCLC group and healthy controls. These observations suggest that BAL cells from patients with lung cancers express a selective secretory activity and that IL-2 is an important regulatory factor of secondary production of IL-6 and NO. Utilization of IL-2 in therapeutic strategy in SCLC can lead to alterations in synthesis/release of biologically active IL-6 and NO that may contribute to the clinical settings.
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PMID:Exogenous interleukin 2 regulates interleukin 6 and nitric oxide but not interferon gamma and tumor necrosis factor alpha production in bronchoalveolar leukocytes from patients with small cell lung cancer. 988 16

The cooperative antitumor effects of IL-12 and IL-15 gene transfer were studied in the N592 MHC class I-negative small cell lung cancer cell line xenotransplanted in nude mice. N592 cells engineered to secrete IL-15 displayed a significantly reduced tumor growth kinetics, and a slightly reduced tumor take rate, while N592 engineered with IL-12 displayed only minor changes in their growth in nude mice. However, N592 cells producing both cytokines were completely rejected, and produced a potent local bystander effect, inducing rejection of coinjected wild-type tumor cells. N592/IL-12/IL-15 cells were completely and promptly rejected also in NK-depleted nude mice, while in granulocyte-depleted animals a slight delay in the rejection process was observed. Immunohistochemical analyses of the N592/IL-12/IL-15 tumor area in intact nude mice revealed the presence of infiltrating macrophages, granulocytes, and NK cells, and expression of inducible NO synthase and of secondary cytokines such as IL-1beta, TNF-alpha, and IFN-gamma, and at higher levels GM-CSF, macrophage-inflammatory protein-2, and monocyte chemoattractant protein-1. In NK cell-depleted nude mice, numerous macrophages and granulocytes infiltrated the tumor, and a strong expression of macrophage-inflammatory protein-2 and inducible NO synthase was also observed. Finally, macrophages cocultured with N592/IL-12/IL-15 produced NO in vitro, and inhibited tumor cell growth, further suggesting their role as effector cells in this model.
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PMID:The combined action of IL-15 and IL-12 gene transfer can induce tumor cell rejection without T and NK cell involvement. 1097 24


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