Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of an extended panel of cytokine genes was investigated by reverse polymerase chain reaction (PCR) in 10 freshly excised melanoma metastases infiltrated by lymphocytes (TIL). cDNA encoding for CD3-delta and tyrosinase could be amplified in all samples, confirming the presence of T lymphocytes and melanoma cells. Cytokine genes possibly transcribed by both cell types, such as GM-CSF, IL-6 and IL-10 could be amplified from 5, 2 and 2 samples respectively. In contrast, IL-1 beta and TNF-alpha mRNA were never detectable, IL-1 alpha, IL-3 and IL-7 mRNA could be observed only in one case each. Transcripts encoding for TGF-beta 1 were observed in 8 samples, while TGF-beta 2 and 3 mRNA were detectable in only 2 specimens. mRNA encoding for cytokine genes typically transcribed by antigen-stimulated T lymphocytes, such as IL-2, IL-4 and IFN-gamma were rarely or never detectable (none, none and 1 of the samples respectively). In one case, where no cytokine gene transcription was detectable at the time of surgery, we addressed the question of the antigenicity of the tumor and of the functional competence of TIL. A primary tumor cell line was generated and cultured TIL were induced to transcribe IL-2 and IFN-gamma genes by incubation with the autologous irradiated tumor cell line, but not with autologous EBV-transformed cells. In these conditions, tumor-specific cytotoxic T lymphocytes (CTL) could be generated only after 3 weekly re-stimulations. In contrast, if autologous irradiated EBV-transformed cells were added to the cultures, specific CTL could be detected after one single tumor stimulation. Thus, signs of active responsiveness in terms of lymphokine gene mRNA are seldom detectable in melanoma metastases. Tumor-specific responses, however, including IL-2 and IFN-gamma gene expression and generation of CTL can be produced in vitro from specimens in which no cytokine gene mRNA is detectable ex vivo.
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PMID:The pattern of cytokine gene expression in freshly excised human metastatic melanoma suggests a state of reversible anergy of tumor-infiltrating lymphocytes. 818 65

This study investigated the generation of primary tumor-specific CTL activity in vitro to several mouse tumors. We report that the development of optimal primary tumor-specific CTL to the P815 mastocytoma, the EL4 thymoma, and the Lewis lung carcinoma is dependent on tumor Ags, on enhancement of T cell costimulation by B7.1, and on exogenous T helper activity in the form of IL-2 and IL-4. A relatively low concentration of IL-2 and IL-4 was required to limit the induction of lymphokine-activated killer cells. In the case of P815, the CTL were directed toward molecularly defined tumor rejection Ags. These primary cultures yielded long term T cell lines that were heterogeneous in fine tumor Ag specificity and in cytokine production.
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PMID:Generation of primary tumor-specific CTL in vitro to immunogenic and poorly immunogenic mouse tumors. 855 87

B16 melanoma-bearing mice were treated with anti-interleukin 4 antibody, indomethacin or its combination to evaluate the ability of the primary tumor to induce lung metastasis and the antitumor host response. Flow cytometry of tumor cells incubated with sera from tumor-bearing mice showed B16 melanoma to induce a significant antitumor humoral response (39.0 +/- 1.1% positive cells versus 1.8 +/- 0.9% in the control). The treatment of tumor-bearing mice with antimouse anti-interleukin 4 monoclonal antibody plus indomethacin significantly increased (P < .01) the mean value of lung metastasis (from 6.1 +/- 3.0 in the controls to 50.8 +/- 21.8). Also, a significant increase in natural cytotoxicity against tumor cells was observed when both peripheral blood mononuclear cells and splenocytes were used as effector cells. In contrast, an antibody-dependent cellular cytotoxicity decrease was found with effector cells from both normal and tumor-bearing mice. In the former, the antibody-dependent cellular cytotoxicity decrease was 49.4% and 58.4% (P < .05) for peripheral blood mononuclear cells and splenocytes, whereas in the second case the decrease was 40.7% (P < .05) and 29.1% (P < .01), respectively. These results suggest that an efficient antibody-dependent cellular cytotoxicity response might be necessary to secure an effective host antitumor immune response.
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PMID:Anti-interleukin 4 antibody and indomethacin synergistic effect on B16 melanoma tumor progression. 893 Jan 48

Stressful events suppress a broad spectrum of immunological responses. However, the effects of stress on the antitumor T cell response against syngeneic tumors have not yet been closely studied. In the present study, we investigated the effects of repeated restraint stress on the antitumor T cell response against syngeneic B16 melanoma. The stress, before and after immunization with tumor cells, decreased the potential of the spleen cells to turn into antitumor cytotoxic T lymphocytes (CTLs) after in vitro restimulation. In a cytokine assay, the stress significantly suppressed the tumor-specific CD4+ T cell-dependent IFN-gamma production of immunized spleen cells. The stress also decreased their spontaneous IL-2 production, but it apparently had no effect on IL-4 production. The in vitro addition of IL-2, however, restored the stress-induced inability of the spleen cells to turn into antitumor CTLs after in vitro restimulation, thus suggesting that stress has no definite effect on tumor-specific CD8+ T cells. Stress had no effect on the natural killer (NK) activity of the spleen cells, but did decrease their responsiveness to poly (I:C), an NK activity augmentator. In addition, stress did not influence primary tumor growth but did decrease the degree of protective immunity at rechallenge. On the other hand, stress elevated the serum level of corticosterone and, in addition, the in vivo administration of dexamethasone, a synthetic glucocorticoid, decreased the capacity of the immunized spleen cells to turn into antitumor CTLs after in vitro restimulation and to produce both IFN-gamma and IL-2 in a manner similar to that of mice burdened by stress. Moreover, stress decreased the potential of spleen cells to produce both IFN-gamma and IL-2 in response to anti-CD3 mAb. Overall, these findings provide evidence that stress significantly impairs the antitumor T cell responses through its suppressive effect on Th1-type CD4+ T cells.
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PMID:Repeated restraint stress impairs the antitumor T cell response through its suppressive effect on Th1-type CD4+ T cells. 949 18

Head and neck squamous cell carcinomas (HNSCCs) are associated with abnormal cell-mediated immunity at the primary tumor site. We investigated tumor-derived cytokines as factors underlying such abnormalities. Cytokine mRNA and protein of eight HNSCC-derived cell lines were tested; reverse transcription-PCR results indicated the presence of mRNAs for interleukin 1alpha (IL-1alpha) and transforming growth factor alpha (8 of 8); transforming growth factor beta and IL-1beta (7 of 8); and IL-4 and IL-6 (4 of 8). IL-2, IFN-gamma, and tumor necrosis factor alpha mRNA were not detected. Supernatants from six of these cell lines were analyzed by ELISA; IL-1alpha, IL-1beta, and IL-6 were found to be markedly increased compared to human papillomavirus-16-immortalized human oral keratinocytes. To determine whether the cell line findings are applicable to primary tumors, we performed immunohistochemical analysis on tumor specimens from 12 patients with invasive HNSCC. Universal intracellular production of IL-1alpha, IL-1beta, and IL-6 protein was detected. We conclude that the aberrant elaboration of biologically active IL-1 and IL-6 may contribute to altered immune status in HNSCC patients.
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PMID:Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens. 967 81

Liver metastasis of primary tumor is a clinically major problem. KRN7000, an alpha-galactosylceramide, significantly augments natural killer (NK) activity of spleen cells and shows strong antitumor activity in mice with lung metastasis of melanoma B16 cells. To test whether KRN7000 has an antitumor activity in mice with hepatic metastasis of tumors, we examined the effect of KRN7000 on NK activity of hepatic mononuclear cells (MNC) and the antitumor activity in mice with liver metastasis of EL-4 cells. The in vivo administration of KRN7000 significantly augmented NK activity of hepatic MNC and inhibited tumor growth of EL-4 cells in the liver more markedly than chemotherapeutic agents, leading to a relatively high rate of cured mice. In addition, it appeared that the KRN7000 treatment is effective in mice with established EL-4 tumors. Moreover, we found that KRN7000 can produce significant amounts of interleukin 2 (IL-2), IL-4, IL-12, and interferon-gamma in a dose-dependent manner. These results suggest that KRN7000 will be useful for the treatment of cancer liver metastasis.
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PMID:Antitumor activity of alpha-galactosylceramide, KRN7000, in mice with EL-4 hepatic metastasis and its cytokine production. 1036 37

The beta-chemokine RANTES was measured in plasma in 43 patients with breast cancer and in 23 patients with cervical cancer, and the RANTES content in primary tumors, tumor metastatic to lymph nodes, and clinically normal skin or pelvic mucosa was measured. In addition, plasma levels were determined in all of the patients for the platelet-derived chemokine beta-thromboglobulin (beta-TG) and for IFN-gamma, interleukin (IL)-2, IL-4, IL-5, and IL-10, along with serum IgE levels and blood eosinophils. Plasma RANTES levels were found to be higher in order of stages IV, III, II, and I of each cancer except for stage I. A marked increase in plasma RANTES level (> 10,000 pg/ml) was found in 27% of patients with progressive malignancy but in none of those in clinical remission. The platelet RANTES content was correspondingly decreased in those patients with increased plasma RANTES levels. Beta-TG showed a pattern similar to RANTES both in plasma and platelets, but with much less dramatic differences between patients with different stages of disease. Other allergic parameters, IgE, eosinophils and plasma IFN-gamma, IL-2, -5, and -10, were not elevated in the cancer patients. The RANTES content was markedly elevated in the primary tumor and metastatic lesions (lymph node or skin) from all of the patients with breast or cervical cancer, irrespective of the plasma RANTES level. In addition, in patients with progressive breast or cervical cancer, but not in patients thought to be cured of these tumors, the RANTES content was markedly increased in clinically normal tissue taken from near the operative site several months postoperatively, as well as in intact skin or mucosa taken perioperatively near the excised tumor. This study suggests an as-yet-undefined but important role played by RANTES in carcinogenesis, as well as the possibility that a RANTES assay in tissue surrounding a tumor or postoperative tumor site may help predict prognosis in these patients.
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PMID:Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. 1123 81

Immunotherapy targeting for the induction of a T-cell-mediated antitumor response in patients with renal cell carcinoma (RCC) appears to hold significant promise. Here we describe a novel RCC vaccine strategy that allows for the concomitant delivery of dual immune activators: G250, a widely expressed RCC associated antigen; and granulocyte/macrophage-colony stimulating factor (GM-CSF), an immunomodulatory factor for antigen-presenting cells. The G250-GM-CSF fusion gene was constructed and expressed in Sf9 cells using a baculovirus expression vector system. The Mr 66,000 fusion protein (FP) was subsequently purified through a 6xHis-Ni2+-NTA affinity column and SP Sepharose/fast protein liquid chromatography. The purified FP retains GM-CSF bioactivity, which is comparable, on a molar basis, to that of recombinant GM-CSF when tested in a GM-CSF-dependent cell line. When combined with interleukin 4 (IL-4; 1000 units/ml), FP (0.34 microg/ml) induces differentiation of monocytes (CD14+) into dendritic cells (DCs) expressing surface markers characteristic for antigen-presenting cells. Up-regulation of mature DCs (CD83+CD19-; 17% versus 6%) with enhanced expression of HLA class I and class II antigens was detected in FP-cultured DCs as compared with DCs cultured with recombinant GM-CSF. Treatment of peripheral blood mononuclear cells (PBMCs) with FP alone (2.7 microg/10(7) cells) augments both T-cell helper 1 (Th1) and Th2 cytokine mRNA expression (IL-2, IL-4, GM-CSF, IFN-gamma, and tumor necrosis factor-alpha). Comparison of various immune manipulation strategies in parallel, bulk PBMCs treated with FP (0.34 microg/ml) plus IL-4 (1000 units/ml) for 1 week and restimulated weekly with FP plus IL-2 (20 IU/ml) induced maximal growth expansion of active T cells expressing the T-cell receptor and specific anti-RCC cytotoxicity, which could be blocked by the addition of anti-HLA class I, anti-CD3, or anti-CD8 antibodies. In one tested patient, an augmented cytotoxicity against lymph node-derived RCC target was determined as compared with that against primary tumor targets, which corresponded to an 8-fold higher G250 mRNA expression in lymph node tumor as compared with primary tumor. The replacement of FP with recombinant GM-CSF as an immunostimulant completely abrogated the selection of RCC-specific killer cells in peripheral blood mononuclear cell cultures. All FP-modulated peripheral blood mononuclear cell cultures with antitumor activity showed an up-regulated CD3+CD4+ cell population. These results suggest that GM-CSF-G250 FP is a potent immunostimulant with the capacity for activating immunomodulatory DCs and inducing a T-helper cell-supported, G250-targeted, and CD8+-mediated antitumor response. These findings may have important implications for the use of GM-CSF-G250 FP as a tumor vaccine for the treatment of patients with advanced kidney cancer.
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PMID:Induction of G250-targeted and T-cell-mediated antitumor activity against renal cell carcinoma using a chimeric fusion protein consisting of G250 and granulocyte/monocyte-colony stimulating factor. 1169 14

Costimulation of tumor T cells by B7.1 has been shown to be important for eliciting cell-mediated anti-tumor immunity. We constructed a stable B7.1 gene transfectant of a poorly immunogenic murine sarcoma, Moloney murine sarcoma virus-induced tumor cell line (MMSV). This transfectant, MMSV-B7.1, failed to produce any tumor development in syngeneic mouse models. When MMSV-B7.1 was simultaneously injected with wild-type MMSV, about half of the coinjected mice remained tumor free and displayed an increase in T cell population, upregulation of the mRNA level of various cytokines such as IL-4, IL-5, IL-10, IL-13, IL-15 and IFN-gamma, and complete rejection of reinjected MMSV. To investigate whether MMSV-B7.1 demonstrates any vaccinal effect, the transfectant was injected following the surgical removal of the primary tumor mass. Following a re-challenge with wild-type MMSV, all vaccinated mice maintained their tumor free status and displayed a rapid recovery of down-regulated cytokine levels. The results suggest that B7.1 vaccination after tumor removal might be useful for the prevention of tumor recurrence.
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PMID:Tumor removal enhances immunity induced by B7.1. 1210 46

Cryoablation is a low-invasive surgical treatment for malignant tumors. It may induce an immunological response leading to the eradication of distant metastases or alternatively it might promote the growth of residual tumors. In this paper we confirm the occurrence of both phenomena and we describe the preventive effect of a protein-bound polysaccharide preparation. Metastatic liver tumors were produced in BALB/c mice by the intrasplenic inoculation of colon 26 cells and cryoablation was carried out using liquid nitrogen (-170 degrees C) applied by a contact method. The value of combining cryoablation with administration of the polysaccharide preparation in the prevention of growth of residual tumors was investigated. It was shown that the number of metastatic liver nodules and the size of the primary tumor at the site of inoculation in the spleen were significantly lower when the volume that was frozen was small. The production by splenocytes of the tumor necrosis factor TNF-alpha, interferon INF-gamma, and the interleukins IL-4 and IL-10 increased significantly after freezing and thawing of the tumor tissue. The polysaccharide treatment significantly reduced the production of IL-4 and IL-10 following cryoablation; the production of TNF-alpha and INF-gamma was slightly promoted; the natural killer and cytotoxic T-cell activities of splenocytes were slightly enhanced. It was concluded that the polysaccharide preparation was beneficial by suppressing IL-4 and IL-10 production and might inhibit the growth of residual tumor that is sometimes induced by large-volume cryoablation.
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PMID:Antitumor effects of residual tumor after cryoablation: the combined effect of residual tumor and a protein-bound polysaccharide on multiple liver metastases in a murine model. 1281 13


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