Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, cytokine release by tumor-draining lymph node cells sensitized in vitro (IVS-TDLN) was examined and correlated with therapeutic efficacy in adoptive immunotherapy. Mice bearing immunologically distinct MCA 207 and MCA 205 sarcoma tumors were utilized in criss-cross experiments. IVS-TDLN obtained from mice bearing 10-day subcutaneous (s.c.) tumors mediated immunologically specific regression of established 3-day pulmonary metastases, but demonstrated non-specific cytolytic reactivity against both tumors in a 4-h 51Cr-release assay. By contrast, these IVS-TDLN cells were found specifically to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) when restimulated in vitro with irradiated tumor cells. To determine the predictive value of tumor-specific cytokine release with in vivo therapeutic efficacy, a kinetic analysis of antitumor activities of TDLN obtained from animals bearing MCA 207 tumors for increasing lengths of time was performed. IVS-TDLN cells from mice bearing day-7, -10 and -14 s.c. tumors manifested tumor-specific release of GM-CSF and IFN gamma, and mediated significant antitumor reactivity in vivo. In contrast IVS-LN cells from day-0 and day-21 tumor-bearing animals did not release significant amounts of GM-CSF and IFN gamma, and were not therapeutically efficacious in vivo. Day-4 IVS-TDLN released high levels of GM-CSF and IFN gamma non-specifically, and were not therapeutic in adoptive immunotherapy at doses effective for day-7 and day-14 IVS-TDLN cells. In other experiments, IVS cells generated from different lymph node groups in animals bearing 10-day established s.c. tumors were examined and found to have unique profiles of cytokine release. In these studies, the ability of IVS cells to release specifically both cytokines as opposed to one was associated with greater therapeutic efficacy on a per cell basis. Our findings suggest that the tumor-specific releases of GM-CSF and IFN gamma are useful parameters to assess the in vivo therapeutic efficacy of immune lymphocytes.
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PMID:Tumor-specific granulocyte/macrophage colony-stimulating factor and interferon gamma secretion is associated with in vivo therapeutic efficacy of activated tumor-draining lymph node cells. 853 78

In humans, tumor necrosis factor (TNF) treatment has been associated with characteristic changes in circulating white blood cell populations (leukopenia followed by leukocytosis) and increased cell-surface expression of integrins. A similar pattern of effects on leukocytes occurs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF treatment. To determine whether these effects were caused directly by TNF or as a result of secondary CSF release, G-GM-, and M-CSF levels were measured after TNF infusion (9.6 x 10(6) U/mg protein; < 5.0 endotoxin U/mg protein) in cancer patients during two phase I trials of TNF. One patient with aggressive fibromatosis was treated with TNF alone (200 micrograms/m2, days 1-5 every third week) and 10 patients (four colon cancer, four head and neck cancer; one melanoma; one sarcoma) received mitomycin C (15 mg/m2, day 1) followed by TNF (60-180 micrograms/m2, days 1-3) every sixth week. All treatments were given IV, mitomycin C over 5 minutes and TNF over 2 hours. Serum samples were collected at times 0 (before mitomycin C and TNF) and 1, 2, 4, 6, 12, and 24 hours after TNF initiation on day 1 and at similar times on subsequent treatment days. M-CSF samples were analyzed by radioimmunoassay (RIA) and G-CSF and GM-CSF by ELISA. The mean baseline M-CSF levels in normal control subjects (n = 12) was 158.4 +/- 36.2 (SD) U/mL, and in pretreatment cancer patients (n = 10) 235.7 +/- 60.9 U/mL (p = 0.004, Wilcoxon test). M-CSF levels increased 4 hours after TNF initiation (mean 354.7 +/- 96.3 U/mL; p = 0.020), remained elevated at 6 hours (305.6 +/- 45.4 U/mL; p = 0.004, Wilcoxon signed-rank test), and subsequently declined. This pattern was seen in all patients treated with TNF, whether treatment was TNF alone or TNF with mitomycin C. In patients treated with mitomycin C and TNF, G-CSF levels increased at 4 hours after TNF initiation (mean 3886 +/- 2009 pg/mL; p = 0.004), remained elevated at 6 hours (mean 2140 +/- 1131 pg/mL; p = 0.004), and subsequently declined. GM-CSF levels were not measurable before or after treatment with TNF. The changes in all three endogenous cytokines were not temporally related to the previously described leukopenia and integrin upregulation on circulating leukocytes and, therefore, appear to be unrelated to this event. However, release of endogenous G-CSF and M-CSF under the influence of TNF does temporally coincide with the previously described leukocytosis, suggesting a possible role for these endogenous cytokines in the release of bone marrow cellular stores.
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PMID:Tumor necrosis factor administration is associated with increased endogenous production of M-CSF and G-CSF but not GM-CSF in human cancer patients. 853 92

Patients with primary metastatic or recurrent rhabdomyosarcoma (RMS) have a very poor prognosis. Since high-dose chemotherapy (HDC) +/- TBI was thought to improve survival, many centers performed this therapy using different types of hematopoietic rescue (auto BM or PBSC, allo BM). This is a retrospective, multi-center analysis of the results of treatment in 36 patients with primary metastatic or relapsed RMS who were given HDC +/- TBI and hematopoietic rescue between 1986 and 1994. The median age was 6 years (< 1-22 years). Primary therapy was given according to either one of the Cooperative German Soft Tissue Sarcoma Studies CWS-81, -86, -91 or the European Study for Stage IV Malignant Mesenchymal Tumors in Childhood. There were 22 alveolar RMS, 13 embryonal RMS and one undifferentiated sarcoma. The indication for HDC was primary metastatic disease (27 patients) or a relapse of a primary localized tumor (nine patients). Thirty-two patients were in 1st or 2nd CR when given HDC and four in VGPR. The median time from last event to HDC was 44 weeks (21-110). HDC consisted of fractionated melphalan ((4 x 30-45 mg/m2), VP16 40-60 mg/kg, carboplatin 3 x 400-500 mg/m2) in 26 patients, 10 of whom received additional FTBI. Seven patients were treated with melphalan alone or in combination with carboplatin. Two patients received cyclophosphamide/busulphan with TLI (total lymphoid irradiation) and one cyclophosphamide with FTBI. Thirty-one patients were given autologous BM or PBSC as hematopoietic rescue and five allogeneic bone marrow from HLA-identical siblings. Fourteen patients received GM-CSF or G-CSF after hematopoietic stem cell transfusion (HSCT). Ten patients received adjuvant IL-2. There was one toxic HDC-related death. Nine patients are alive and free of disease with a median observation time of 57 months (32-108). The median time from HDC to relapse was 4 months (1-17). The tumor recurred in the majority of patients at previously known sites; in three cases new metastatic sites were observed. Patients with primary localized tumors who had been treated with HDC because of relapse did slightly better (four of nine alive with NED) than patients with primary metastatic disease (five of 27 alive with NED). HDC is still of uncertain value in the therapy of poor-risk rhabdomyosarcoma and should be performed only as part of controlled clinical trials.
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PMID:Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. 902 50

Effects of Phytolacca acinosa polysaccharides I (PAP-I), 5 approximately 40 mg/kg in timing of 7 times/wk, 3 times/wk and 1 time/wk on their antitumor efficiency in Sarcoma-180 bearing mice were comparatively investigated. The results confirmed that PAP-I (10 mg/kg, 3 times/wk) reached its optimal antitumor efficiency. Concanavalin A-, lipopolysaccharides-induced lymphocyte proliferation and the IL-2 production were tested in normal mice which were treated with PAP-I, 5 approximately 50 mg/kg in timing of 1 time/wk and 3 times/wk. The results showed that PAP-I could augment lymphocyte proliferation and IL-2 production in the group treated with PAP-I in timing of once a week. However, in the group 3 times/wk, PAP-I could significantly weaken lymphocyte proliferation and IL-2 production. Further studies on IL-1, TNF and IL-6 secreted from macrophages and the level of CSF activity in serum of normal mice with different schedules showed that PAP-I (10 mg/kg, 3 time/wk) was the best one in regulating the production of IL-1, TNF, IL-6 and CSF activity. M-CSF was confirmed in the serum by using monoclonal antibody of IL-3, GM-CSF and polyclonal antibody of M-CSF. These results suggested that the antitumor effect of PAP-I, may be mainly related to its augmenting effect on macrophages in mice.
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PMID:Effects of Phytolacca acinosa polysaccharides I with different schedules on its antitumor efficiency in tumor bearing mice and production of IL-1, IL-2, IL-6, TNF, CSF activity in normal mice. 913 6

We examined the relative efficacy of allogeneic versus syngeneic fibroblasts admixed with tumor cells as a vaccine to induce antitumor T-cell reactivity. Allogeneic (3T3) or syngeneic (BLK) fibroblasts transfected to secrete equivalent amounts of GM-CSF were admixed with either D5 melanoma or MCA 207 sarcoma and inoculated s.c. into the flanks of C57BL/6 mice. Vaccine-primed lymph node (LN) cells were examined for in vivo antitumor reactivity in an adoptive transfer model. At fibroblast: tumor cell ratios of < or=1, allogeneic and syngeneic granulocyte macrophage colony-stimulating factor-secreting fibroblasts enhanced T-cell reactivity to tumor cells. However, at ratios of 2.4, the adjuvant effect induced by granulocyte macrophage colony-stimulating factor was not evident. Instead, we observed increased alloreactivity of primed LN cells against 3T3 targets as assessed by cytotoxicity and cytokine release assays, which was not observed with syngeneic fibroblasts. Moreover, with increasing numbers of allogeneic fibroblasts, there was a skewing of the T-cell Vbeta repertoire. These latter cells responded to tumor stimulation with the release of greater amounts of interleukin 10, which may account for the diminished antitumor reactivity observed in vivo. Allogeneic fibroblasts transduced to secrete interleukin 2 or IFN-gamma also induced diminished tumor reactivity of primed LN cells. Syngeneic fibroblasts are superior to allogeneic fibroblasts as vehicles to deliver cytokines in tumor vaccines.
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PMID:Reduced efficacy of allogeneic versus syngeneic fibroblasts modified to secrete cytokines as a tumor vaccine adjuvant. 924 54

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and systemic low dose rIL-2 effectively eradicates pulmonary metastases of the murine MCA-105 sarcoma. We described earlier that host CD8+ T cells are critical for tumor eradication and that successful treatment is associated with production of high levels of IFN-gamma and granulocyte/macrophage (GM)-CSF by donor TIL in vitro. Here, we propose the mechanism through which adoptively transferred Thy-1.1+ TIL induce a host antitumor response in congenic Thy-1.2+ tumor-bearing mice. Donor Thy-1.1+ TIL were detected at the tumor site 12 h after transfer. These Thy-1.1+ cells produced IFN-gamma and GM-CSF in situ. The percentage of Thy-1.1+ TIL at the tumor site increased up to 16.4 +/- 4.9% 24 h after transfer but decreased to undetectable levels thereafter. In contrast, the percentages of host cells producing IFN-gamma and GM-CSF continued to increase at the tumor site. These increases were significantly higher in TIL + rIL-2-treated mice compared with untreated mice and rIL-2-treated mice 48 h after TIL transfer. The appearance of IFN-gamma+ and GM-CSF+ cells was followed by a large influx of host CD4+, CD8+, and Thy-1.2+ TIL and eventually by tumor eradication. This response was tumor specific since TIL obtained from MCA-205 did not induce high levels of IFN-gamma and GM-CSF and did not induce tumor eradication of MCA-105 tumor. Coinjection of Thy-1.1+ TIL and anti-IFN-gamma or anti-GM-CSF mAb significantly inhibited antitumor efficacy of the TIL + rIL-2 treatment. We conclude that successful adoptive immunotherapy in this model is mediated through cytokine production by adoptively transferred TIL that induce a host T cell-dependent antitumor response.
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PMID:Successful adoptive cellular immunotherapy is dependent on induction of a host immune response triggered by cytokine (IFN-gamma and granulocyte/macrophage colony-stimulating factor) producing donor tumor-infiltrating lymphocytes. 955 89

The development of genetically modified "whole" tumor cell vaccines for cancer therapy relies on the efficient transduction and expression of genes by vectors. In the present study, we have used a disabled infectious single cycle-herpes simplex virus 2 (DISC-HSV-2) vector constructed to express cytokine or marker genes upon infection. DISC-HSV-2 is able to infect a wide range of tumor cells and efficiently express the beta-galactosidase reporter gene, granulocyte-macrophage colony-stimulating factor (GM-CSF), or IL-2 genes. Gene expression occurred rapidly after infection of tumor cells, and the level of production of the gene product (beta-galactosidase, GM-CSF, or IL-2) was shown to be both time-and dose-dependent. Vaccination with irradiated DISC-mGM-CSF or DISC-hIL-2-infected murine tumor cells resulted in greatly enhanced immunity to tumor challenge with live parental tumor cells compared with control vaccines. When used therapeutically to treat existing tumors, vaccination with irradiated DISC-mGM-CSF-infected tumor cells significantly reduced the incidence and growth rates of tumors when administered locally adjacent to the tumor site, providing up to 90% protection. The prophylactic and therapeutic efficacy of DISC-mGM-CSF-infected cells was shown initially using a murine renal cell carcinoma model (RENCA), and the results were confirmed in two additional murine tumor models: the M3 melanoma and 302R sarcoma. Therapy with DISC-infected RENCA "whole" cell vaccines failed to reduce the incidence or growth of tumor in congenitally T-cell deficient (Nu+/Nu+) mice or mice depleted of CD4+ and/or CD8+ T-lymphocytes, confirming that both T-helper and T-cytotoxic effector arms of the immune response are required to promote tumor rejection. These preclinical results suggest that this "novel" DISC-HSV vector may prove to be efficacious in developing genetically modified whole-cell vaccines for clinical use.
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PMID:Preclinical evaluation of "whole" cell vaccines for prophylaxis and therapy using a disabled infectious single cycle-herpes simplex virus vector to transduce cytokine genes. 1074 37

Human T cell leukemia virus type I (HTLV-I) or its transcriptional transactivator, Tax1, was introduced into a human osteosarcoma cell line, HOS, and a Moloney murine sarcoma virus-positive HOS cell line, S+L-HOS. These HTLV-I- or Tax1-expressing cells were injected subcutaneously into nude mice to investigate the effects of HTLV-I on their tumorigenicities. HOS cells did not form any tumors even in the presence of HTLV-I or Tax1. S+L-HOS cells did form small tumors in two-thirds of nude mice. Infection of S+L-HOS cells with HTLV-I, or transduction of Tax1 into S+L-HOS cells markedly facilitated the tumor formation, and the tumor-bearing mice showed marked splenomegaly and neutrophilia. Elevated levels of granulocyte colony-stimulating factor (G-CSF) were detected in sera of these mice and also in the culture supernatants of Tax1-expressing human cells, suggesting that G-CSF in the mouse sera was produced by the human cells. In sera of some mice with splenomegaly and neutrophilia, high levels of murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) were observed, suggesting that Tax1 produced by human cells induced mouse cells to produce mGM-CSF. Only S+L-HOS cell lines expressing Tax1 showed high tumorigenicity in nude mice. Thus, this system will be a useful model of tumor formation, splenomegaly and neutrophilia dependent on Tax1.
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PMID:Rapid tumor formation and development of neutrophilia and splenomegaly in nude mice transplanted with human cells expressing human T cell leukemia virus type I or Tax1. 1094 44

Despite numerous strategies, the cure of multiple myeloma remains a difficult challenge. Recent approaches have involved dose-intensive therapy followed by stem cell transplantation, most often with autologous stem cells (ASCT). Although ASCT is of benefit, it is not considered curative. Between 1988 and 1995, we utilized an aggressive three-drug conditioning regimen followed by ABMT using marrow purged with either 4-hydroperoxycyclophosphamide (4-HC) or mafosphamide (MAF). Twenty-nine of 42 patients who had first received VAD (14 patients) or VAD followed by cyclophosphamide (7 g/m2 i.v.) + dexamethasone (40 mg/day p.o. x4) + GM-CSF (15 patients) met the eligibility criteria needed to undergo bone marrow harvest and ABMT, ie < or =10% marrow plasma cells and > or =50% decrease in paraprotein level. Alpha-interferon maintenance therapy was given post ABMT. Median follow-up is 7.5 years (range 5.0-11.25). Six early and two late non-relapse deaths occurred; 15 patients have relapsed. Seven patients remain in continuous CR (five) or PR (two), including three with stage IIIB disease at diagnosis. One patient developed a soft tissue sarcoma 8 years post ASCT. Although this protocol produced excessive toxicity compared with current approaches, the results demonstrate that dose-intensive therapy and ASCT can produce durable remission in this disease. Further development of dose-intensive strategies is warranted.
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PMID:Prolonged survival after intensive therapy and purged ABMT in patients with multiple myeloma. 1104 67

A recent phase I study of aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with malignant metastases to the lungs demonstrated excellent tolerance and possible efficacy. This therapy was offered to other patients who refused "standard" treatment or when no effective therapy was available. Forty-five patients were treated; 40 had pulmonary metastases. Aerosolized GM-CSF (250 microg/dose) was administered twice a day using a 1 week on, 1 week off schedule. The mean interval between diagnosis and therapy was 32 months. Twenty-four patients had disease stabilization or partial regression. The mean duration of benefit was 10 months. This benefit was noted in 8 of 13 with a sarcoma, 6 of 14 with melanoma, and 5 of 12 with renal cell carcinoma. Eighteen patients reported mostly self-limiting toxicities. The frequency of certain melanoma-specific T lymphocytes in 1 patient with stable disease was found to have increased 10-fold after therapy. Aerosolized GM-CSF appears to have limited but promising efficacy in treatment of pulmonary metastatic disease. In one patient, we have evidence of upregulation of melanoma-specific cytotoxic T-cells. Further study is warranted to understand the impact of this therapy on the natural history of metastatic cancer.
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PMID:Aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) therapy in metastatic cancer. 1452 78


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