Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The levels of expression of histocompatibility antigens on the cell membrane and their gene expression in non-metastatic and in highly metastatic Friend leukemia cells (FLC) were measured and the levels of expression of these antigens were correlated with the different in vivo behaviour of the tumor cells. Highly metastatic in vivo passaged FLC (either interferon-sensitive 745 or interferon alpha/beta-resistant 3Cl-8 cells) expressed higher levels of class I H-2K and H-2D antigens on their cell membrane with respect to the non-metastatic in vitro passaged counterparts. The increased expression of H-2 class I antigens was associated with an increased transcription of H-2K and H-2D genes. As both in vitro and in vivo passaged FLC have been shown to be resistant in vitro to the natural killer (NK) cell activity, we tried to correlate the levels of expression of histocompatibility antigens with the in vivo clearance of [125I]UDR-labeled FLC. However, no correlation was found between the levels of expression of H-2 antigens and the in vivo clearance of tumor cells. In fact, in vivo passaged FLC (tested either after 1 or after 15 in vitro passages) expressed virtually identical levels of H-2 antigens; however, the freshly explanted in vivo passaged FLC exhibited markedly lower levels of clearance from the lung, spleen and liver (when injected i.v. in DBA/2 mice) with respect to the corresponding FLC cultivated for several passages in vitro. Pretreatment of in vitro passaged 745 FLC with either interferon alpha/beta or interferon gamma resulted in the acquisition of some metastatic potential of FLC to the liver when interferon-treated FLC were subsequently injected i.v. in DBA/2 mice; such in vitro treatments resulted in a 2-3-fold increase in the expression of H-2K antigens versus the control untreated FLC. We suggest that such increases could represent some advantages for the homing properties of tumor cells and/or for the tumor progression, by mechanisms different from the resistance to the NK cells.
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PMID:Studies on the expression of H-2 antigens in non-metastatic and highly metastatic Friend erythroleukemia cells: correlation with the in vivo behaviour of tumor cells. 247 72

T cells infiltrating (T-TIL) B cell non-Hodgkin's lymphomas (NHL) are thought to represent a local host response to the tumor. However, tumor progression in the presence of this T cell infiltrate suggests that the T-TIL may be functionally impaired. To address this issue we determined whether response to stimulation of T-TIL from 25 patients with NHL through the T cell receptor (TCR/CD3) and the interleukin-2 (IL-2) receptor (IL-2R) was intact, since activation of these receptors is important for proliferation and cytokine production. Our results demonstrate defects in response to stimulation via TCR/CD3 and the IL-2R in T-TIL cells from patients with NHL that were not observed with T cells from the peripheral blood. T-TIL showed minimal proliferation to anti-CD3 and only modest proliferation to IL-2 alone or when combined with anti-CD3. Moreover, cytokine production in T-TIL was impaired since stimulation through the TCR/CD3 complex did not induce mRNA for interferon gamma (IFN gamma), IL-2, IL-4 or IL-10. The functional unresponsiveness of these cells may be linked to altered signalling through the TCR/CD3 since an abnormal tyrosine phosphorylation pattern was detected in T-TIL after stimulation with anti-CD3.
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PMID:Responses to T cell receptor/CD3 and interleukin-2 receptor stimulation are altered in T cells from B cell non-Hodgkin's lymphomas. 755 87

Unregulated expression of epidermal growth factor receptor (EGF-R) is a common event in neoplastic transformation and has been shown to be associated with melanocytic tumor progression. Modulation of such a receptor by pharmacological agents could therefore be of clinical interest. We have studied EGF-R expression, its response to epidermal growth factor (EGF) and modulation effects by interferon gamma (IFN gamma) on human melanoma cells. Addition of EGF, anti-EGF and anti-EGF-R antibodies had no effect on proliferation of six melanoma cell lines tested. We report in this communication that EGF-R expression on human melanoma cells can be modulated by IFN-gamma. In the melanoma cell lines treated with IFN gamma, proliferative behavior was not affected; however, we demonstrate a downregulation of EGF-R expression on the protein level, by immunohistochemistry and flow cytometric analysis, and an accumulation of EGF-R mRNA by Northern blot analysis. The results suggest that IFN gamma downregulates EGF-R expression at a posttranscriptional level on human melanoma cells. This EGF/EGF-R interaction and its modulation by IFN gamma on human melanoma cells needs to be further clarified regarding its in vivo significance for the treatment and prognosis of malignant melanoma.
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PMID:Interferon-gamma downregulates epidermal growth factor receptors on human melanoma cells. 775 29

Neuroblastoma is one of the commonest solid tumors in children. Conventional therapeutic approaches, such as surgery, chemotherapy and radiotherapy, fail to control tumor progression in stage III and IV patients. The search for novel therapeutic strategies should necessarily take into account immunotherapy and gene therapy. Here the theoretical bases for the development of such approaches are discussed. Studies carried out with neuroblastoma (NB) cell lines have shown that neoplastic cells express a wide array of potential tumor associated antigens (TAA) but are devoid of HLA molecules which are necessary for TAA presentation to the host immune system. Transfection of NB cells with the interferon gamma gene appears a promising approach, since this cytokine up-regulates the expression of class I HLA molecules in NB cells. Other cytokines of potential interest for gene transfer studies are interleukin 2 (IL2) and interleukin 12 (IL12).
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PMID:[Rational bases for new approaches to the therapy of pediatric solid tumors: immunotherapy and gene therapy]. 797 43

We have measured the levels of interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta, and IL-2 in the whole blood cell culture supernatants of 43 tumor patients undergoing a treatment with biological response modifiers or a conventional therapy with 5-fluorouracil and leucovorin. In the blood cell cultures of the 16 patients who received 5-fluorouracil and leucovorin IFN gamma levels decreased (P < or = 0.01) and TNF alpha levels rose (P < or = 0.05) during each therapy cycle. However, in the blood samples a declining number of total leukocytes and lymphocytes was measured (P < or = 0.05). Progressive disease could be correlated to a tendency towards lower IFN gamma levels in the pretherapeutic cultures of these patients. The second group analyzed consisted of 8 patients receiving a low-dose IL-1 beta therapy. In this group we found either an unchanged or an augmented IFN gamma production of the blood cells during treatment. In the group of 13 patients receiving low-dose recombinant IL-2 (< or = 4.5 x 10(6) IU m-2 day-1) significantly increasing IFN gamma levels were seen in the blood cell cultures during the therapy (P < or = 0.05), although total leukocyte counts decreased. In this group, 4 had stable disease for at least 2 months and 9 patients had tumor progression under therapy. In the cultures of the latter a tendency towards lower IFN gamma values was found. Finally, the cytokine production in the blood cell cultures of 6 patients receiving a combination therapy of IFN alpha and high-dose IL-2 was studied. During this therapy a dramatically reduced production not only of IFN gamma but also of all other measured cytokines was found. In this group all patients had tumor progression under therapy. It is concluded that the measurements of cytokine production in a reproducible whole blood culture system may be useful for monitoring immunological therapies and may help us to find out which doses of biological response modifiers have enhancing or suppressive effects on the functions of the immune cells.
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PMID:Cytokine production in whole blood cell cultures of patients undergoing therapy with biological response modifiers or 5-fluorouracil. 833 80

This study explored the use of interleukin 2 (IL-2) and interferon gamma (IFN-gamma) gene-modified tumor cells as cellular vaccines for the treatment of bladder cancer. The mouse MBT-2 tumor used is an excellent model for human bladder cancer. This carcinogen-induced tumor of bladder origin resembles human bladder cancer in its etiology and histology, and responds to treatment in a manner similar to its human counterpart. Using retroviral vectors, the human IL-2 and mouse IFN-gamma genes were introduced and expressed in MBT-2 cells. The tumor-forming capacity of the cytokine gene-modified MBT-2 cells was significantly impaired, since no tumors formed in mice injected intradermally with either IL-2- or IFN-gamma-secreting cells, using cell doses far exceeding the minimal tumorigenic dose of parental MBT-2 cells. Furthermore, mice that rejected the IL-2- or IFN-gamma-secreting tumor cells became highly resistant to a subsequent challenge with parental MBT-2 cells, but not to 38C13 cells, a B cell lymphoma of the same genetic background. To approximate the conditions as closely as possible to the conditions prevailing in the cancer patient, inactivated cytokine-secreting cells were used to treat animals bearing tumors established by orthotopic implantation of MBT-2 cells into the bladder wall of the animal. Treatment of mice carrying a significant tumor burden with IL-2-secreting MBT-2 cells had a significant inhibitory effect on tumor progression with extended survival. Moreover, in 60% of the mice the tumor regressed completely and the animals remained alive and free of detectable tumor for the duration of the observation period. Treatment of tumor-bearing animals with IL-2-secreting MBT-2 cells was superior to the use of cisplatin, a chemotherapeutic agent used in the treatment of bladder cancer. The therapeutic effect of IFN-gamma-secreting cells was minimal and treatment with unmodified MBT-2 cells had no effect on tumor growth or survival, showing that the parental MBT-2 cells were nonimmunogenic in this experimental setting. Most importantly, mice that exhibited complete tumor regression after treatment with IL-2-secreting MBT-2 cells became resistant to a subsequent challenge with a highly tumorigenic dose of parental MBT-2 cells, indicating that long-term immunological memory was established in the "cured" mice.
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PMID:Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells. 845 7

Human melanoma is a highly immunogenic tumor capable of inducing a specific immune response. A number of melanoma-associated antigens have been characterized during the past several years and can be classified into two groups: differentiation antigens-present also in normal melanocytes-and tumor-specific antigens, which, with the exception of testis, are present only in tumor cells. In a previous publication [Kirkin A. F., Petersen T. R., Olsen A. C., Li L., thor Straten P., Zeuthen J. (1995) Cancer Immunol Immunother 41:71] we have described the production of clones of cytotoxic T lymphocytes (CTL) against the highly immunogenic human melanoma cell line FM3. Using these clones we have defined four previously unknown melanoma-associated antigens, which could be subdivided into differentiation and progression antigens. In the experiments reported in this paper, we have further compared CTL clones from different groups and shown that the sensitivity of melanoma cells to CTL that recognize differentiation or progression antigens is differentially modulated during tumor progression as well as by the lymphokines interferon gamma (IFN gamma) and interleukin-10 (IL-10). The interaction of CTL clones recognizing progression antigens was strongly increased after treatment of melanoma cells with IFN gamma, while the recognition by CTL clones specific for differentiation antigens either was unchanged or significantly decreased. IL-10 treatment of melanoma cells induced up-regulation with respect to recognition by CTL clones specific for differentiation antigens without affecting the recognition of melanoma cells by CTL clones specific for progression antigens. Using cellular systems at different stages of tumor progression, we demonstrated that the progressed state of melanoma cells is associated with increased sensitivity to recognition by CTL clones detecting progression antigens, and with decreased sensitivity to CTL clones recognizing differentiation antigens. Mimicking tumor progression, treatment with IFN-gamma induced apparent down-regulation of differentiation antigens. A hypothesis is suggested in which IFN-gamma plays different roles in the immune response against poorly immunogenic and highly immunogenic melanoma cells, increasing the progression of poorly immunogenic tumor cells or promoting a strong immune response and regression of highly immunogenic melanoma cells.
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PMID:Differential modulation by interferon gamma of the sensitivity of human melanoma cells to cytolytic T cell clones that recognize differentiation or progression antigens. 866 67

Circulating immune markers sICAM-1, sELAM-1, sMHC-I, beta 2-MG, sCD4 and sCD8 were evaluated prior to and during immunotherapy with biologically active doses of interferon gamma (IFN-gamma) in 16 patients with advanced renal cell carcinoma (RCC) over a period of 12 months. Compared to 20 healthy controls, significantly (P < 0.01) elevated baseline levels of circulating adhesion molecules sICAM-1 (mean 1166 vs 230 ng/ml) and sELAM-1 (70 vs 17 ng/ml) were found in all patients. Compared to responders (n = 2) or patients with stable disease (n = 2), progressive disease during therapy (n = 12) was associated with significantly (P < 0.05) higher mean concentrations of sICAM-1 (1574 vs 962 ng/ml) and sELAM-1 (86 vs 46 ng/ml). Pretherapeutic and intratherapeutic levels of sMHC-I among the RCC patients were significantly (P < 0.05) lower than among the controls (0.41 vs 0.8 ng/ml). sCD4 levels clearly showed the same tendency (24 vs 33 U/l). sCD8 baseline levels, by contrast, were significantly (P < 0.05) elevated (564 vs 336 U/l), reflecting either activation of the NK-cell subset or increased synthesis of CD8+ T-suppressor cells. Again, significantly (P < 0.05) higher intratherapeutic sCD8 concentrations were observable with progressive disease than with response to therapy or stable disease (721 vs 355 U/l). Interestingly, although the biologically active dose of IFN-gamma was defined by an increase in beta 2-MG release of at least 30% within 48 h after injection, none of the other markers showed any significant alteration following IFN-gamma administration, suggesting that IFN-gamma in vivo does not produce changes in circulating markers of activation that might be expected on the basis of its effects in vitro. The finding of significantly elevated concentrations of sICAM-1, sELAM-1 and sCD8 in the presence of low sCD4 and sMHC-I levels might be of clinical significance for indicating ongoing tumor progression.
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PMID:Circulating immune markers in advanced renal cell carcinoma during immunotherapy with interferon gamma. 874 Sep 79

The microbial immunostimulant OK-432 has been studied intensively in preclinical systems and has shown promise as an anticancer agent in trials that have been conducted over the past 20 years in Japan. To date, no systematic dose response evaluation of this agent has defined its dose-limiting toxicity or immunobiological activity. A phase IA study has been conducted in 25 patients with metastatic cancer at the University of Pittsburgh Cancer Institute Melanoma Center, establishing 30 KE as the maximal tolerable dosage, on the basis of cutaneous reactions. Subsequently, 48 patients with resected high-risk melanoma participated in a phase IB study of OK-432. This study has evaluated the immunomodulatory activity of OK-432 at five dosages ranging from 1 KE to 20 KE, administered ID twice weekly for 3 months. A formal analysis of the treated population in comparison to the randomized control group has been conducted, and profound immunological effects have been defined in the group of patients treated with OK-432. Patients who participated in this trial had a significant depression of OK-432-inducible cytokine production (interleukin-1 beta, interferon gamma, and tumor necrosis factor alpha) at baseline. Treatment with OK-432 reversed this deficit for interferon gamma (IFN gamma) production in a dose-dependent manner, and mitigated the inhibition for interleukin-1 (IL-1) across all dosage groups. The impact of OK-432 upon other immunological functions of the treated cohorts is more variable, with durable suppression of mononuclear cell superoxide production, and in vitro cytotoxicity to tumor. Immunological characteristics of the entire cohort demonstrate a strong and significant correlation of elevated blood CD16+ cell counts and natural killer activity with early tumor progression and death due to melanoma. Favorable prognosis is associated with monocyte capacity to produce tumor necrosis factor (TNF), and polymorphonuclear leukocyte formylmethionyl-leucylphenylalanine-inducible superoxide release. This study reveals several new immunological correlates of tumor progression and lethal outcome in resected high-risk melanoma. It demonstrates that the depressed IL-1, TNF, and IFN gamma release associated with melanoma may be mitigated by treatment with OK-432. This study has defined treatment and dose response patterns of immunomodulation associated with one of the most complex immunological agents yet evaluated in phase IB trials, in a well-defined population of high-risk patients with resected melanoma.
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PMID:Phase IB trial of picibanil (OK-432) as an immunomodulator in patients with resected high-risk melanoma. 919 73

We previously reported [Chakrabarti et al. (1992) Cell Immunol 142:54; 144:455] that, in a murine B lymphoma model 2C3, idiotype (Id)-specific CD8+ cytotoxic T lymphocytes (CTL) are generated in mice following hyperimmunization with irradiated tumor cells, and that they are effective in tumor rejection. The present study reveals that 2C3-specific CTL are also induced in spleens during tumor progression, but are not sustained. At the early stage of tumor growth, the splenic T cells following a 5-day incubation in vitro with killed 2C3 tumor targets, produce high levels of cytokines, namely interleukin-4 (IL-4), IL-10 and interferon gamma (IFN gamma). Their cytotoxic T lymphocyte (CTL) activity and cytokine levels, except IL-2, sharply decline at the late stage when the mice are increasingly moribund. Although the decline in cytokine level is also evident with CD4+ T cells, a precipitous and concurrent decrease occurs primarily in the IL-4 level with both CD4+ and CD8+ T cells of late-tumor-bearing animals (TBA). Study with the unseparated splenocytes also reveals that sevenfold less IL-4 is produced at the late stage. Furthermore, the cytotoxicity of CTL from late TBA can be effectively restored by addition of supernatants from the splenocyte culture of early TBA, or by IL-4, but not by IFN gamma and IL-10. In addition, only IL-4-activated CD8+ T cells from the late TBA are found, by Winn assay, to be protective in vivo. Thus it appears that IL-4, required to sustain antitumor CTL activity, is consumed by T and possibly other cells at the late stage of tumor growth, thereby compromising host immunity against the tumor. We contend that induction or maintenance of protective immunity depends not only on the tumor antigen but also on the specific cytokine milieu in a tumor-bearing host.
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PMID:Interleukin-4 is effective in restoring cytotoxic T cell activity that declines during in vivo progression of a murine B lymphoma. 924 64


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