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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor growth decreases T-cell recognition of self major histocompatibility complex (MHC) class II molecules by inducing changes in splenic macrophage (M phi) phenotype and function. The current investigation shows tumor-induced alterations in autorecognition also are associated with changes in responsiveness to and production of granulocyte-M phi colony-stimulating factor (GM-CSF). In contrast to normal host (NH) M phi, tumor-bearing host (TBH) M phi failed to express higher MHC class II molecule density after exposure to GM-CSF. Autoreactive T cells stimulated by either NH or TBH M phi were suppressed by GM-CSF. Inhibition of prostaglandin E2 (PGE2) synthesis reversed M-CSF-induced suppression of autoreactivity to NH M phi and, to a lesser extent, to TBH M phi. When TBH autoreactive T cells were stimulated by TBH M phi, autoreactivity increased when GM-CSF was added and PGE2 synthesis was inhibited. Although GM-CSF can contribute to tumor-induced suppression, it did not affect the contribution of GM-CSF during autorecognition. Increased GM-CSF production was responsible, at least in part, for the TBH M phi-mediated suppression. Low concentrations of GM-CSF were produced endogenously by tumor isolates, and GM-CSF production was significantly increased when isolates were stimulated with lipopolysaccharide. Autoreactive T cells stimulated solely by TBH M phi produced more GM-CSF than autoreactive T cells stimulated by NH M phi. Cultures supplemented with several concentrations of NH or TBH M phi produced similar amounts of GM-CSF in a dose-dependent manner. Inhibition of PGE2 synthesis by NH and TBH M phi reduced GM-CSF production equally. Collectively, these results suggest that during tumor growth, responsiveness to and production of GM-CSF alters recognition of self MHC class II molecules.
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PMID:Tumor growth changes responsiveness to and production of granulocyte-macrophage colony-stimulating factor during recognition of self MHC class II molecules. 129 76

The present study was designed to evaluate the effects of a recombinant human G-CSF (rhG-CSF) and a mutein G-CSF (KW-2228) on leucopenia and tumor growth in mice treated with 5-fluorouracil (5-FU). In normal mice, the number of leucocytes (white blood cell, WBC) reached the peak 12 hours after a single injection of either type of G-CSF and decreased to the normal level after 24 hours. Daily administration induced a continuous increase in the WBC count, however, administrations at intervals did not. Meth-A fibrosarcoma was subcutaneously inoculated into the backs of syngeneic BALB/c mice. The mice were treated with 5-FU alone or with G-CSFs. Chemotherapy with 5-FU alone resulted in leucopenia and an insignificant inhibition of tumor growth. The conjunctive administration of G-CSFs with 5-FU resulted in a significantly augmented inhibition of tumour growth, and leukopenia was not seen. This augmenting effect was more prominent with KW-2228. These results suggest that in 5-FU chemotherapy G-CSFs may be beneficial in restoring the number of leucocytes from leucopenic state and in augmenting the tumor inhibitory effect. Furthermore, KW-2228 may be more beneficial than the natural type rhG-CSF.
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PMID:Comparative effects of a recombinant and a mutein type of granulocyte colony stimulating factor on the growth of Meth-A fibrosarcoma with 5-fluorouracil chemotherapy. 137 28

Recent advances in our understanding of the hemolymphopoietic growth factors has revolutionized knowledge of blood cell development, the immune system, and of tumor cell biology. However, the rapid translation of these insights from basic research to the clinic has been perhaps the most dramatic part of the story. Commercially available erythropoietin has become established for the treatment of the anemia of end-stage renal disease, and promises to be of value in the supportive care of patients with cancer and perhaps other chronic diseases. It likely will be increasingly utilized for enhancing autologous blood donation and for perioperative management. Both GM-CSF and G-CSF only recently released by the FDA for specific clinical indications, though there are a variety of potential applications (Table 12). It is clear that G-CSF is the therapy of choice for most neutropenias and that both agents have effects in diminishing the myelotoxicity and mucositis seen after aggressive chemoradiotherapy. However, it is important to note that as yet there is no evidence that the use of either G-CSF or GM-CSF has resulted in increased cure rates or, in fact, increased survival in patients with various malignancies. It would appear that both G-CSF and GM-CSF will, in fact, allow dose escalation and/or diminished toxicity of various chemotherapeutic regimens. However, there are important considerations in the overall place of these cytokines with regard to treatment of human disease. A major goal in the therapy of patients with malignancy is obviously prolongation of life and cure. If, in fact, escalation of doses of chemotherapeutic agents does not result in increased tumor responses or cures then the use of these growth factors will have a relatively trivial impact on the care of cancer patients. In addition, the disturbing observations of receptors for these growth factors on various tumor cell lines and of varying degrees of in vitro tumor cell proliferative responses raises the possibility that in some situations they may actually stimulate tumor growth. This is an unknown which has not been adequately evaluated in any clinical study to date and which may vary from tumor to tumor. For example, if these cytokines increase tumor growth rate by 20-30% (an effect which would probably not be detected in the clinical studies to date) while allowing an escalation of chemotherapy doses it is possible that there would be no significant beneficial effect.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hematopoietic growth factors. 142 40

Tumor-bearing host (TBH) macrophages (M phi) suppress T cell alloresponses, and this study suggests granulocyte-macrophage colony-stimulating factor (GM-CSF), a molecule associated with suppressive M phi activity during tumor growth, signals more immunosuppression. In the absence of M phi, GM-CSF increased T cell proliferation in response to alloantigen. However, TBH M phi-mediated suppression of allorecogntion was further induced by GM-CSF. Allogeneic mixed lymphocyte reaction (MLR) cultures, containing normal host (NH) M phi, were either unaffected or enhanced. Prostaglandin E2 (PGE2), a highly suppressive monokine that decreases alloreactivity, did not seem to be involved in the suppression caused by the TBH M phi/GM-CSF interaction. M phi-CSF (M-CSF) addition to cultures did not reverse the suppression caused by TBH M phi and GM-CSF, and inhibition of PGE2 synthesis did not change the response to M-CSF. TBH Ia- M phi, a suppressor population that predominates among splenic M phi during tumor growth, demonstrated significantly lower reactivity in the presence of GM-CSF. In contrast, alloresponses suppressed by NH Ia- M phi demonstrated higher reactivity in the presence of GM-CSF. The data collectively suggest that TBH M phi respond differently to GM-CSF, and that tumor-induced changes in GM-CSF responsiveness affect M phi accessory ability.
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PMID:Tumor growth changes the contribution of granulocyte-macrophage colony-stimulating factor during macrophage-mediated suppression of allorecognition. 145 14

We have assayed modulation of clonal growth of cell lines from human solid tumors in vitro by recombinant human interleukin-6 (rhIL-6), rhIL-3, rh granulocyte-macrophage colony-stimulating factor (GM-CSF), rhG-CSF, rhM-CSF, and rh erythropoietin. Effects of hematopoietic growth factors were also tested in the tritiated thymidine uptake assay. No reproducible and significant modulation of clonal growth was found with rhIL-6, rhM-CSF, and rhEPO. The other cytokines showed stimulation of colony formation in some cell lines from colorectal adenocarcinomas and bladder and lung cancers with the following order of activity: rhIL-3 greater than or equal to rhGM-CSF greater than rhG-CSF. Growth stimulation was only found in clonal assays; it was abolished by neutralizing antibodies and was highly dependent on culture conditions. Stimulation could be masked by elevation of serum concentration and there was an inverse correlation between spontaneous plating efficacy of the control cells and growth stimulation by the factor with the highest activity of the colony-stimulating factor at suboptimal growth conditions. Growth inhibition by the cytokines was not observed. We could not establish autocrine loops for the growth modulation by the cytokines in the cell lines tested so far. Furthermore, we xenotransplanted some responsive cell lines into athymic mice and observed their in vivo growth under systemic application of rhIL-3 and rhGM-CSF or vehicle. There was no significant alteration of the tumor growth by these cytokines at plasma levels sufficient for in vitro growth stimulation. In conclusion, tumor growth stimulation by rhGM-CSF and rhIL-3 as potential hazards for their clinical application in cancer patients in conjunction with cytotoxic chemotherapy is unlikely.
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PMID:Effects of hematopoietic growth factors on malignant nonhematopoietic cells. 155 74

Implantation of genetically manipulated fibroblasts is now coming considered to be one of the important methods for gene therapy. Before the clinical application of this method, we still need to resolve several problems encountered. We have recently developed a model system for the fibroblast-mediated cytokine supplementation gene therapy. BMGNeo (bovine papilloma virus-derived plasmid) (gifted from Dr. Karasuyama) was used for expression of hG-CSF cDNA or hIFN-alpha cDNA (gifted from Dr. Nagata). The two plasmid DNAs (BMGNeoG-CSF and BMGNeoIFN) were individually transfected into NIH/3T3 fibroblasts by the calcium phosphate coprecipitation method. Cell clones producing a large amount of G-CSF or IFN-alpha were selected by the enzyme immunoassay methods and were called G-CSF3T3 or IFN3T3 respectively. Nude mice implanted with G-CSF3T3 highly produced G-CSF in vivo. Remarkable increases in both blood neutrophils and spleen hematopoietic stem cells/progenitor cells (CFU-S, BFU-E, CFU-E, CFU-GM and CFU-MK) were observed. To regulate the production of G-CSF by G-CSF3T3 in vivo, we developed a diffusion chamber system as the cells can be treated easily. We could control the peripheral neutrophil count in nude mice. In the same manner, IFN3T3 was implanted in nude mice bearing a CML cell line, KU812. KU812 tumor growth was significantly suppressed by implantation of IFN3T3 into the chamber. The fibroblast-mediated cytokine supplementation gene therapy might be useful for the treatment of patients requiring for continuous dosing of cytokines.
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PMID:[Implantation of genetically manipulated fibroblasts into mice as a model of gene therapy--supplementations of human granulocyte colony-stimulating factor (hG-CSF) and interferon-alpha (IFN-alpha)]. 165 96

Myelosuppression following intensive chemotherapy in cancer patients is associated with increased morbidity and mortality. Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), alone or in combination with interleukin-1 (IL-1), have been shown to counteract myelosuppression resulting from some, but not all, chemotherapeutic regimens. In an attempt to apply these findings to intensive therapy with proliferation-dependent chemotherapeutic drugs such as fluorouracil (5-FU), we investigated combination biochemotherapy in a murine model. Female CD8F1 [(BALB/c X DBA/8)F1] mice bearing first-passage transplants of spontaneous CD8F1 breast tumors were treated intraperitoneally once a week for 3 successive weeks with a course of 5-FU alone or with a course of 5-FU in combination with recombinant human interleukin-1 beta (rHuIL-1 beta) alone or in combination with CSFs. rHuIL-1 beta alone or in combination with rHuG-CSF or recombinant murine GM-CSF significantly improved tumor growth inhibition (60% vs. 90%) and survival (20% vs. 90%-100%), increased the maximally tolerated dose of 5-FU, accelerated recovery of neutrophil counts in peripheral blood, and reduced duration of significant neutropenia and loss of body weight (29% vs. 10% loss). Clinical trials of IL-1 have been initiated in patients with advanced cancer receiving multiple courses of high-dose 5-FU.
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PMID:Hematologic effects of interleukin-1 beta, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in tumor-bearing mice treated with fluorouracil. 169 5

We have investigated the effect of granulocyte colony-stimulating factor (G-CSF) delivery at the site of tumor growth by transducing, via retroviral vector, the human (hu) G-CSF gene into the colon adenocarcinoma C-26 and assaying the ability of transduced cells to form tumors when injected into syngeneic mice. As a control, the same tumor cells were infected with retroviruses engineered to transduce an unrelated gene, the human nerve growth factor receptor, or carry the neomycin resistance gene only. Only cells transduced with the huG-CSF were unable to develop tumors, although huG-CSF was expressed and produced at low level as estimated by both RNA analysis and enzyme-linked immunosorbent assay, indicating that G-CSF can exert an antitumor effect at a physiological dose. Implication of G-CSF as mediator of tumor inhibition was proven by reversing the nontumorigenic phenotype of G-CSF-expressing cells with anti-huG-CSF monoclonal antibody injected at the tumor site. No tumors were formed by injecting C-26 infected cells into nu/nu mice, while neoplastic nodules appeared after injection into sublethally irradiated mice; such tumors, however, regressed when mice normalized their leukocyte counts after irradiation. Tumors were also formed after injection of a mixture of infected and uninfected C-26 cells, although critical delay in tumor formation occurred when infected cells were 10 times more represented in the mixture. Histological examination of tissues surrounding the site of injection showed infiltration of neutrophilic granulocytes, whose number correlated with that of G-CSF-expressing C-26 cells in the injected mixture. These results indicate that G-CSF may have a potent antitumoral activity when released, even at low doses, at the tumor site. The antitumoral effect is mediated by recruitment and targeting of neutrophilic granulocytes to G-CSF-releasing cells.
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PMID:Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in vivo. 170 52

Leukocytosis associated with malignant disease has been known as a paraneoplastic syndrome and occurs occasionally in patients with oral malignancies. In this study, mechanisms underlying leukocytosis associated with malignancy was investigated, using a squamous cell carcinoma of the maxilla from a patient who manifested marked leukocytosis. When the patient's tumor was inoculated into nude mice, it formed squamous cell carcinoma (MH85) and induced leukocytosis and splenomegaly. Leukocytosis and splenomegaly paralleled tumor growth. Surgical excision of MH85 tumor resulted in a dramatic reduction of leukocyte count and spleen weight, indicating an involvement of humoral mediators released by MH85. MH85 cells conditioned medium (MH85CM) were shown to contain granulocyte-colony stimulating factor (G-CSF) activity, which is a potent growth factor specific for granulocytes. These results suggest G-CSF or G-CSF like substance secreted by MH85 cells is responsible for leukocytosis in MH85 bearing nude mice (MH85 mice) and in the patient. MH85 cell growth was stimulated by G-CSF and inhibited by anti-G-CSF antibody, thus suggesting that G-CSF like substance is a autocrine growth factor for MH85 cells. Splenectomized MH85 mice developed less severe leukocytosis than did non-splenectomized mice. This finding indicated that not only G-CSF like substance secreted by MH85 cells but other humoral factors released by the hyperplastic spleen contribute to the development of leukocytosis. Splenic monocytes derived from MH85 mice and MH85CM-stimulated splenic monocytes showed increased secretion of tumor necrosis factor (TNF) and interleukin-1 (IL-1), both of which have been reported to induce neutrophilia in animals. Moreover, injection of anti-TNF-antibody into neutrophilic MH85 mice significantly, although not completely, decreased leukocyte count. Thus, it seemed likely that increased secretion of TNF and IL-1 by spleen cells that are stimulated by humoral factors released from MH85 also contributes to the progression of leukocytosis. In splenectomized mice, enlargement of MH85 tumor was retarded and metastases were impaired compared these in nonsplenectomized mice. Coculture of splenocytes from MH85 mice with normal spleen cells, inhibited blastogenesis in response to mitogen. The result suggests that splenocytes from MH85 mice played as immune suppressive cells. MH85CM conferred immune suppressive activity on normal spleen cells. This suppressor cell-inducing factor (SCIF) in MH85CM was found to have an apparent molecular weight of approximately 25kd, and its biological activity was neutralized by anti-G-CSF antibody. Therefore, SCIF secreted by MH85 cells was likely to be G-CSF like substance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Studies on the pathophysiology of paraneoplastic syndromes: both cancer cells and host immune cells are responsible for the pathophysiology of leukocytosis associated with oral cancer]. 172 87

We here describe the isolation, characterization, profile of lymphokine expression and T-cell-receptor gene rearrangement pattern of 444P.3, a CD3+ CD4+ CD8- 4B4+ interleukin-2 (IL-2)-dependent clone derived from the malignant ascites of a patient with renal cell cancer. The 444P.3 clone exhibited unique antitumor specificity between days 45 and 84 in culture and then lost its lytic, but not its proliferative, capacity. To our knowledge this is the first description of a specific antitumor reaction in a patient with renal cell cancer against autologous tumor. IL-2-expanded 444P.3 cells, tested on day 104 in culture, expressed mRNA for tumor necrosis factor (TNF), IL-2 and tumor growth factor beta (TGF-beta) but not for IL-1, lymphotoxin or granulocyte/macrophage-colony stimulating factor (GM-CSF). The parental noncloned population expressed mRNA for TNF, lymphotoxin, GM-CSF and TGF-beta but not for IL-1 beta or IL-2. Analysis of established human T cell clones should include profiles of lymphokine secretion in addition to growth and proliferation patterns, antitumor activity and surface phenotype. Such characterization of clones may provide a better understanding of the immunoregulatory role and functional potential of various T cell subsets involved in human antitumor reactivity.
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PMID:Lymphokine mRNA profile and functional analysis of a human CD4+ clone with unique antitumor specificity isolated from renal cell carcinoma ascitic fluid. 196 60


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