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)

A 66-year-old woman with hypopharyngeal cancer was treated with recombinant interferon-gamma (KW-2202). r-IFN-gamma was administered at a dose of 1-8 X 10(6) U/body every day for six weeks by i.v. drip infusion. After the start of the therapy both the primary tumor and metastatic lymph nodes showed remarkable regression and PR was obtained. Observed side effects, which included fever and hepatic function disorder, were slight and transient. Immunological studies were also carried out on the patients and the results were reported. Further investigation will be necessary in order to confirm the efficacy of the drug and to compile data on immunological parameters.
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PMID:[A case of hypopharyngeal cancer responding to recombinant interferon-gamma (KW-2202)]. 310 10

The effect of recombinant gamma-interferon (IFN-gamma) on established human colon carcinoma cell lines as well as fresh tumor cells from colon carcinoma patients has been investigated with respect to growth inhibition, enhancement of HLA expression, and modulation of immunogenicity. A direct antiproliferative activity of IFN-gamma was observed in five of seven cell lines tested, with a reduction of [3H]thymidine incorporation between 30 and 90%. Depending on the cell line, the IFN-gamma doses required for maximal inhibition varied between 20 and 2 X 10(4) units/ml. Independent of this effect, IFN-gamma enhanced the expression of HLA-A,B,C antigens in all cells investigated and induced expression of HLA-DR in three of seven carcinoma cell lines. Antigenic modulation of Class I and II major histocompatibility complex antigens was paralleled by an enhancement of the in vitro immunogenicity in three of four established carcinoma lines and in three of three cases, using cells derived from primary tumor cultures. Induction or enhancement of both proliferative and cytolytic T-cell responses was obtained in allogeneic and in autologous mixed-lymphocyte tumor cell cultures.
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PMID:Differential gamma-interferon response of human colon carcinoma cells: inhibition of proliferation and modulation of immunogenicity as independent effects of gamma-interferon on tumor cell growth. 316 Apr 56

Most tumors grow progressively and overwhelm the host. The rare but documented cases of spontaneous regression of primary tumors are indicative of the potential of tumor-bearing hosts to develop a significant antitumor response. Because most tumors grow progressively in the host, it is not surprising that the majority of studies have focused on T lymphocytes that infiltrate these tumors. Although these studies have generated significant and useful information during the period of tumor growth, they can only speculate on the mechanisms that are involved in tumor rejection. We have used a well developed sponge model of concomitant tumor immunity that allows us to compare the immunologic events that occur during tumor progression vs rejection. In this model, an animal harboring a primary EMT6 mammary tumor is challenged with a secondary tumor implant through a pre-implanted gelatin sponge. During the manifestation of concomitant tumor immunity, the secondary tumor is rejected and the effector cells mediating the response are retained within the sponge matrix. Using this model we analyzed the TCR usage, cytotoxic activity of lymphocytes, and cytokine production at both tumor sites. The data revealed that tumor-rejecting lymphocytes isolated from the site of secondary tumor implant were cytotoxic toward EMT6 cells, whereas tumor-infiltrating lymphocytes isolated from the progressing primary tumor were not. Interestingly, the TCR-V beta repertoire of the tumor-infiltrating lymphocytes and tumor-rejecting lymphocytes were identical with V beta 1 and V beta 8 being predominant at both sites. Furthermore, the rejection site showed higher gene expression of IFN-gamma, TNF-alpha, and IL-10 whereas TGF-beta expression was slightly higher in the progressing tumors. These findings suggest that the disparate effector functions observed during tumor progression vs rejection are not caused by different T cell phenotypes but may be due instead to influences exerted by cytokines produced at the tumor sites.
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PMID:T lymphocytes infiltrating sites of tumor rejection and progression display identical V beta usage but different cytotoxic activities. 770 35

Production of granulocyte-macrophage (GM) colony-stimulating factor by murine metastatic Lewis lung carcinoma cells (LLC-LN7) increases the number and distribution of GM progenitor cells that are suppressive to T cell responsiveness to interleukin 2 (IL-2). The presence of these GM suppressor cells can be diminished by treatment of LLC-LN7-bearing mice with low doses of 100 units IFN-gamma plus 10 units tumor necrosis factor alpha (TNF-alpha). The aim of this study was to determine whether treatment of LLC-LN7-bearing mice with IFN-gamma/TNF-alpha to diminish GM suppressor cell presence would increase the responsiveness to IL-2 immune stimulatory therapy (100-1000 IU, twice daily for 5 days). Treatment first with IFN-gamma/TNF-alpha and then also with low dose IL-2 increased both the numbers of CD4+ and CD8+ cells within the tumor and the levels of their expression of the p55 IL-2 receptor. These intratumoral T cells also had an increased cytolytic capacity toward autologous tumor cells and an increased capacity to proliferate and secrete IL-2. Such effects were observed to a lesser extent in mice that were treated with either IFN-gamma/TNF-alpha alone or with low doses of IL-2 only. The combination treatment regimen of IFN-gamma/TNF-alpha and then IL-2 was also significantly more effective at reducing the size of the primary tumor and the formation of metastatic lung nodules than were the individual treatments. These results show that treatment to minimize the presence of GM suppressor cells enhances the effectiveness of IL-2 to stimulate anti-tumor immune responses and to diminish tumor growth and metastasis.
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PMID:Treating tumor-bearing mice with low-dose gamma-interferon plus tumor necrosis factor alpha to diminish immune suppressive granulocyte-macrophage progenitor cells increases responsiveness to interleukin 2 immunotherapy. 785 Aug 4

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

Interleukin (IL)-7 has been evaluated for its influence, alone or in combination with local hyperthermia (LH), on B16a melanoma-bearing mice. Six- to eight-week-old C57BL/6J male mice were inoculated s.c. with 5 x 10(5) tumor cells into the left hind limb. Mice were randomly divided into four groups, and treated s.c. with IL-7 (5 ng) or saline as control, twice a day for three weeks beginning eight days after tumor inoculation. LH, using hot water circulator at 43 +/- 0.2 degrees C for 30 min, was induced to the limb with tumor twice a week for two weeks. Size of the primary tumor was measured every other day for five weeks. Mice were sacrificed five weeks after tumor inoculation. The size of the primary tumor and the number of lung metastases were reduced in mice treated either with IL-7 or LH alone. As a control for IL-7, granulocyte colony stimulating factor (G-CSF) alone had no effect on primary tumor size or number of lung metastases. The greatest antitumor effect was observed in mice treated with IL-7 in combination with LH. Survival was prolonged significantly only in mice treated with IL-7 plus LH compared with that of mice treated with saline. Decreased natural killer (NK) cell activity, number of Thy1.2 cells, and ratio of L3T4+/Lyt2+ cells were associated with tumor growth. These parameters were restored in mice treated with IL-7 plus LH. Increases in levels of IL-1 alpha, IL-6, tumor necrosis factor (TNF alpha) and interferon (IFN gamma) were associated with an increase in the survival of tumor-bearing mice treated with IL-7 and/or LH. These results suggest that changes in T-cell, NK cell and cytokines such as IL-1 alpha, IL-6, TNF-alpha and IFN-gamma in response to IL7 and/or LH might account for prolonged survival of B16a melanoma-bearing mice and that IL-7 might be useful as a potential antitumor agent combined with other therapy in certain malignant solid tumors with metastases.
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PMID:Antitumor effect of interleukin 7 in combination with local hyperthermia in mice bearing B16a melanoma cells. 824 52

Tumor specific immunity is mediated by CTL that recognize peptide Ag in the context of MHC class I molecules and by Th cells that recognize peptide Ag in the context of MHC class II molecules. To clarify the relative importance of MHC class I and II Ag in tumor rejection, we transfected a K1735 melanoma that did not express constitutively either MHC class I or II Ag with H-2Kk and/or I-Ak genes and determined their tumorigenicity. K1735 transfectants expressing either Kk or Ak Ag alone produced tumors in normal C3H mice, whereas most transfectants that expressed both molecules were rejected in normal C3H mice but produced tumors in nude mice. However, the Ak Ag requirement can be substituted by IL-2 because transfection of Kk-positive/Ak-negative K1735 cells with the IL-2 gene also resulted in abrogation of tumorigenicity in normal C3H mice but not in nude mice. Similarly, transfection of Kk-negative/Ak-positive K1735 cells with IFN-gamma gene resulted in induction of MHC class I Ag as well as rejection of these tumors in normal C3H mice. The rejection of K1735 transfectants expressing Kk and Ak Ag in normal C3H mice required both CD4+ and CD8+ T cells. In addition, the transplantation immunity induced by K1735 transfectants expressing both Kk and Ak Ag completely cross-protected mice against challenge with Kk-positive transfectants but only weakly protected them against challenge with parental K1735 cells or Ak-positive transfectants. These results indicate that expression of either MHC class I or II Ag alone is insufficient to cause the rejection of K1735 melanoma in syngeneic hosts and that both Ag are necessary. In addition, our data suggest that the failure of Kk-positive K1735 cells to induce a primary tumor rejection response in normal C3H mice may result from their inability to induce the helper arm of the antitumor immune response.
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PMID:Rejection of K1735 murine melanoma in syngeneic hosts requires expression of MHC class I antigens and either class II antigens or IL-2. 832 26

Unfractionated spleen cells taken from tumor-bearing mice 2 weeks after tumor implantation contained tumor-primed T cells which produced cytokines including IL-2 and IFN-gamma when cultured in vitro. With progressive tumor growth this initial lymphokine-producing capacity decreased. Here, we investigated the ability of IL-12 to (i) restore suppressed IFN-gamma production, (ii) cause tumor regression and (ii) induce anti-tumor protective immunity. Addition of rIL-12 to spleen cell cultures from 4- to 10-week-old tumor-bearing mice resulted in a striking enhancement in the production of IFN-gamma compared with cultures of these cells in the absence of rIL-12 or of normal spleen cells in the presence of rIL-12. Five i.p. injections of rIL-12 into mice bearing s.c. tumors induced complete tumor regression. This was found when rIL-12 was given at early (1-2 weeks), intermediate (4-5 weeks) or even late (7 weeks) stages of tumor growth. Furthermore, IL-12-treated mice which rejected the primary tumor exhibited complete resistance to a rechallenge with the same tumor but did not reject a second syngenetic tumor. Immunohistochemical analyses following IL-12 treatment revealed that CD4+ and CD8+ T cells infiltrate the tumor. More importantly, IFN-gamma mRNA expression was observed in fresh tumor masses from tumor-bearing mice receiving IL-12 treatment. The importance of IFN-gamma was further demonstrated by the observation that the systemic administration of anti-IFN-gamma mAb prior to IL-12 treatment completely abrogated the anti-tumor effect of IL-12. Thus, these results indicate that administration of modest levels of rIL-12 to tumor-bearing mice results in tumor regression through mechanisms involving reversal of suppressed IFN-gamma production by anti-tumor T cells and the establishment of a tumor-specific protective immune response.
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PMID:Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells. 852 11

In some human tumors, reduced or defective MHC class I surface expression has been attributed to functional deficiencies of the genes of the antigen-processing machinery, the proteasome subunits low molecular weight (LMP)-2 and LMP-7, as well as the peptide transporters associated with antigen processing (TAP)-1 and TAP-2. Using normal epithelial kidney cells (MZ1851NN) and renal cell carcinoma cell lines established from the primary tumor (MZ1851RC) and a lymph node metastasis (MZ1851LN) of the same patient, we investigated whether the modulation of MHC class I antigens, TAP and LMP molecules, occurs during transformation and subsequent progression. The mRNA and protein expression of MHC class I heavy and light chain TAP and LMP was strongly reduced in MZ1851RC when compared to the corresponding normal kidney cells MZ1851NN, and this suppression was even more pronounced in the metastatic cell line MZ1851LN. In addition, the activity of the TAP molecules, as measured by peptide translocation assays, was also markedly diminished in MZ1851RC compared to MZ1851NN cells and was further down-regulated in cells of the metastatic lesion. MHC class I surface expression was enhanced by either culturing MZ1851RC and MZ1851LN cells at 26 degrees C instead of 37 degrees C or by incubation of both cell lines with class I-specific binding peptides, whereas MHC class I surface expression of MZ1851NN cells was not affected under these culture conditions. IFN-alpha and in particular IFN-gamma treatment enhances the steady-state mRNA and/or protein levels of TAP, LMP, and MHC class I genes of MZ1851 cell lines but had no additional effect on the stability of MCH class I surface expression. These data indicate that malignant transformation and subsequent in vivo selection of renal tubular cells can lead to the recovery of carcinoma cells that show stable expression of an immune escape phenotype. Deficiencies associated with this phenotype involve all levels of the MHC class I-restricted antigen presentation machinery, are at least partially reversible by IFN treatment, and are even more pronounced in cells that had acquired metastatic potential.
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PMID:Analysis of the major histocompatibility complex class I antigen presentation machinery in normal and malignant renal cells: evidence for deficiencies associated with transformation and progression. 862 Apr 89

The efficacy of recombinant human gamma interferon (rh IFN-gamma) was evaluated for the treatment of human pleural adenocarcinoma in a patient-like nude mice model which is constructed by surgical orthotopic implantation (SOI) of histologically-intact human tumor tissue. The human non-small-cell lung cancer cell line H-460 was used for the study. Gamma interferon was tested in three different dosages (25,000 U, 50,000 U and 100,000 U) versus an untreated control through i.p. injection twice a day for five days, which was started 48 hours after SOI; The results showed that IFN-gamma can prolong the survival time of the tumor-bearing animals. The symptoms and signs of hypoxia such as restricted physical activity and cyanosis due to primary tumor growth in the thoracic cavity as well as cachexia developed much earlier in the control than in the IFN-gamma-treated mice. The mice in the control group had succumbed by day-23 after tumor implantation, however at that time 67% of the mice in the 100,000 U-treated group, 15% of the mice in the 50,000 U-treated group, and 16% of the mice in the 25,000 U-treated group were still alive. The orthotopically-transplanted tumor grew rapidly and metastasized to the lung and liver in the untreated control. In the IFN-gamma-treated groups both primary tumor growth and metastasis were reduced, probably accounting for the increased survival rate. The results demonstrated dose-dependent efficacy of IFN-gamma in suppressing symptomology, primary tumor growth, invasiveness and metastasis of the human lung cancer cell line H 460, and increased survival of the tumor-bearing animals. These results suggest clinical trials of IFN-gamma should begin for treatment of pleural adenocarcinoma for which there is no current effective therapy.
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PMID:Interferon gamma is highly effective against orthotopically-implanted human pleural adenocarcinoma in nude mice. 891 49


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