Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are very few studies describing the preventive effect of macrophage colony-stimulating factor (M-CSF/CSF-1) on chemotherapy-induced infection. In this study, we evaluated the changes in superoxide anion production by granulocytes before and after chemotherapy in ovarian cancer patients and investigated the preventive effect of M-CSF on chemotherapy-induced febrile neutropenia. Three courses of chemotherapy [paclitaxel 180 mg/m(2) and carboplatin (area under the curve; AUC 5)] were administered to 32 ovarian cancer patients, and seven patients presented febrile neutropenia. In the 25 afebrile patients, the percentage of superoxide anion production by granulocytes was significantly decreased from 86.5 +/- 7.7 (%) to 75.1 +/- 8.8 (%) at day 7 and 71.0 +/- 6.3 (%) at day 14 without administration of CSF. However, in the patients who presented febrile neutropenia, it was more severely decreased from 86.8 +/- 6.8 (%) to 60.0 +/- 9.9 (%) at day 7 and 56.8 +/- 5.0 (%) at day 14 without administration of CSF. When M-CSF was administered to all patients in the next course with the same dose of chemotherapy, the incidence of febrile neutropenia was significantly decreased (P = 0.0195), and the duration of fever (>or= 38.0 degrees C) and high serum C-reactive protein (CRP) (>or= 2.0 mg/dl) were also significantly shortened (P = 0.0023, P = 0.0051). Moreover, in these M-CSF-treated patients, the percentage of superoxide anion production by granulocytes was maintained at the level before chemotherapy. These findings indicate that severe impairment of granulocyte function leads to febrile neutropenia, and that M-CSF reduces the incidence of febrile neutropenia by maintaining or improving granulocyte function.
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PMID:Macrophage colony-stimulating factor prevents febrile neutropenia induced by chemotherapy. 1171 51

We evaluated the influence of M-CSF treatment on granulocyte functions in patients with ovarian cancer. Eighteen patients with ovarian cancer received two consecutive courses of chemotherapy (16 cases, CAP therapy and two cases, CP therapy) at 4-week intervals. M-CSF (8 million U/day) was infused for 7 days starting from the next day after chemotherapy. Superoxide anion production by isolated peripheral blood granulocytes, their phagocytosis, and expression of cell adhesion molecules such as CD11a, CD11b, and CD18 on granulocytes were measured by flow cytometry. Cytokine (IL-8, G-CSF, and GM-CSF) levels in peripheral blood monocyte (PBM) culture supernatants were measured by enzyme-linked immunosorbent assay in 5 out of 18 cases. The levels of CD11a, CD11b and CD18 expression on peripheral blood granulocytes and superoxide anion production by granulocytes were significantly suppressed by chemotherapy without CSF support. The levels of CD11a and CD18 expression on granulocytes were significantly enhanced by administration of M-CSF. When M-CSF was added to cultured PBM, the level of IL-8 in the supernatant increased with the concentration of M-CSF. When IL-8 was added to cultured granulocytes, the levels of CD18 expression on granulocytes and superoxide anion production by granulocytes were significantly increased. These observations suggest that M-CSF enhances the production of IL-8 from monocytes in vivo, thereby improving chemotherapy-induced granulocyte dysfunction.
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PMID:Macrophage colony-stimulating factor restored chemotherapy-induced granulocyte dysfunctions: role of IL-8 production by monocytes. 1178 72

Ideally, vaccines should be designed to elicit long-lived immunity. The goal of this study was to determine whether HER-2/neu peptide-specific CD8+ T-cell immunity could be elicited using an immunodominant HER-2/neu-derived HLA-A2 peptide alone in the absence of exogenous help. Granulocyte macrophage colony-stimulating factor (GM-CSF) was used as adjuvant. Six HLA-A2 patients with HER-2/neu-overexpressing cancers received 6 monthly vaccinations with a vaccine preparation consisting of 500 microg of HER-2/neu peptide, p369-377, admixed with 100 microg of GM-CSF. The patients had either stage III or IV breast or ovarian cancer. Immune responses to the p369-377 were examined using an IFN-gamma enzyme-linked immunosorbent spot assay. Before vaccination, the median precursor frequency (range), defined as precursors per 10(6) peripheral blood mononuclear cell, to p369-377 was 0 (no range). After vaccination, the median precursor frequency to p369-377 in four evaluable patients was 0 (0-116). Overall, HER-2/neu peptide-specific precursors developed to p369-377 in two of four evaluable subjects. The responses were short-lived and not detectable at 5 months after the final vaccination. Immunocompetence was evident, because patients had detectable enzyme-linked immunosorbent spot responses to tetanus toxoid and influenza. These results demonstrate that HER-2/neu MHC class I epitopes can induce HER-2/neu peptide-specific IFN-gamma-producing CD8+ T cells. However, the magnitude of the responses were low, as well as short-lived, suggesting that CD4+ T-cell help is required for lasting immunity to this epitope.
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PMID:Immunization of cancer patients with a HER-2/neu, HLA-A2 peptide, p369-377, results in short-lived peptide-specific immunity. 1200 13

Cloned T9 glioma cells (T9-C2) expressing the membrane form of macrophage colony stimulating factor (mM-CSF) inoculated subcutaneously into rats do not grow and glioma-specific immunity is stimulated. Immunotherapy experiments showed that intracranial T9 tumors present for one to four days could be successfully eradicated by peripheral vaccination with T9-C2 cells. CD4+ and CD8+ T splenocytes from immunized rats, when restimulated in vitro with T9 cells, produced interleukin-2 and -4. Protective immunity against intracranial T9 gliomas could only be adoptively transferred into naive rats by the CD4+ splenocytes obtained from T9-C2 immunized rats. Rats immunized by the T9-C2 tumor cells also resisted two different syngeneic gliomas (RT2 and F98) but allowed a syngeneic NUTU-19 ovarian cancer to grow. Such cross-protective immunity against unrelated gliomas suggests that mM-CSF transfected tumor cells have immunotherapeutic potential for use as an allogeneic tumor vaccine.
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PMID:T9 glioma cells expressing membrane-macrophage colony stimulating factor produce CD4+ T cell-associated protective immunity against T9 intracranial gliomas and systemic immunity against different syngeneic gliomas. 1214 31

To determine the toxicity and immunogenicity of the HER-2/neu, HLA-A2-restricted peptide E75 in patients with metastatic breast and ovarian cancer, 14 patients were vaccinated with escalating amounts of E75 (100, 500, and 1000 microg) mixed with 250 microg granulocyte macrophage colony-stimulating factor as adjuvant. Each vaccine dose was administered in a total volume of 1.5 ml divided into four intradermal injections and administered weekly for 4 weeks, followed by monthly boosts for a total of 10 injections. Vaccinations were well tolerated without significant toxicity. Blood was drawn before, at 8 weeks, and up to 13-16 months after vaccination for measurement of cellular immunity. Seven of 8 patients tested had significant delayed type hypersensitivity to E75 defined as >5 mm induration. Peripheral blood mononuclear cells from 5 of 9 patients tested proliferated to E75 with a stimulation index of > or = 2.0. Of 8 vaccinated patients tested for induction of a CTL response, 4 responded to stimulation by autologous dendritic cells plus cytokines by eliciting E75-specific lytic activity consistent with the presence of activated/memory cells, 2 others after in vitro stimulation with E75 + interleukin-12 +/- anti-CD152(33KD), whereas 2 others did not respond. Four patients with E75-specific CTLs present specifically recognized E75 on indicator tumors as demonstrated by cold-target inhibition of tumor lysis. These 4 patients showed E75-specific IFN-gamma production. peripheral blood mononuclear cell from 3 of these patients proliferated to E75, but stimulation indices were higher in the prevaccine samples. All 4 of the patients showed DTH responses to E75. These results demonstrate that vaccination with E75+ granulocyte macrophage colony-stimulating factor can induce both peptide-specific IFN-gamma and epitope specific CTLs, which lyse HER-2/neu+ tumors in stage IV patients.
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PMID:Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer. 1242 28

We performed a randomized double blind study between 1992 and 1995 in which 214 patients with FIGO stage I to III ovarian cancers received administration of 10(6) units (low dose group) or 8x10(6) units (high dose group) of macrophage colony-stimulating factor (M-CSF) after cyclophosphamide/adriamycin/cisplatin (CAP) therapy. The period required to finish a set of intensive chemotherapy, which was the primary endpoint, was significantly shortened (p=0.0004), and the incidence of febrile neutropenia significantly decreased (p=0.04). In this study, we followed the patients for a prolonged period. The patients were divided into two groups: patients with complete tumor excision and those with incomplete excision, then the relapse rate and survival rate 5 years after initiation of the clinical study were compared. The relapse rate tended to be lower in the high dose group than in the low dose group in patients with no residual tumor (p=0.0750). However, there was no difference in the relapse rate between the two dose groups in patients with residual tumor. Although there were no significant differences in the survival rate between the high and low dose groups in patients with or without residual tumor, the survival rate in mucinous adenocarcinoma patients with no residual tumor was 64.3% in the low dose group (n=14) and 92.3% in the high dose group (n=14), showing a significantly higher rate (p=0.0436), and the survival rate tended to be higher in the high dose group in patients with serous adenocarcinoma (p=0.0786). Furthermore, in patients aged 40 years or younger with no residual tumor, the survival rates were 73.9 and 100% in the low and high dose groups, respectively, showing a significantly higher rate in the high dose group (p=0.0310). Our results suggest that administration of M-CSF can improve the long-term prognosis of ovarian cancer patients with no residual tumor, but further prospective randomized trials with a primary endpoint of relapse-preventing effect are needed.
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PMID:Clinical usefulness of macrophage colony-stimulating factor for ovarian cancers: Long-term prognosis after five years. 1246 57

The purpose of this study was to clarify the effects of mirimostim (macrophage colony-stimulating factor; M-CSF) on immunological functions after chemotherapy. The percentage of natural killer (NK) cells in peripheral blood mononuclear cells (PBMCs), NK cell activity, T-helper cell 1/T-helper cell 2 (Th1/Th2) ratio, and superoxide anion production by granulocytes (granulocyte function) were measured as immunological parameters before and after chemotherapy in 44 patients with primary ovarian cancer who received at least three consecutive courses of postoperative chemotherapy. Patients were observed during the first course of chemotherapy, and 39 patients who presented grade III or IV neutropenia were entered into this study and randomly allocated to an M-CSF-administered group (group 1; 19 patients) and a non-M-CSF-administered group (group 2; 20 patients) for the second course. For the third course, a crossover trial was conducted. In the observation period, chemotherapy significantly impaired the immunological parameters. In particular, those parameters were significantly decreased at day 14 compared to the level before chemotherapy. The values of the parameters of group 1 were significantly higher than those of group 2. In the course of chemotherapy during which M-CSF was administered, 19 of the 39 patients presented grade IV neutropenia, and received granulocyte colony-stimulating factor (G-CSF) between days 7 and 14. We compared the changes of those immunological parameters in the M-CSF alone group and the M-CSF + G-CSF group, and found that the concomitant use of G-CSF did not further improve the parameters. These results indicate that chemotherapy markedly impaired the immunological functions, and that the administration of M-CSF significantly improved the impaired immunological functions.
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PMID:Mirimostim (macrophage colony-stimulating factor; M-CSF) improves chemotherapy-induced impaired natural killer cell activity, Th1/Th2 balance, and granulocyte function. 1296 81

Imatinib is a tyrosine kinase inhibitor that suppresses the growth of bcr-abl-expressing chronic myeloid leukemia (CML) progenitor cells by blockade of the adenosine triphosphate (ATP)-binding site of the kinase domain of bcr-abl. Imatinib also inhibits the c-abl, platelet-derived growth factor (PDGF) receptor, abl-related gene (ARG) and stem-cell factor (SCF) receptor tyrosine kinases, and has been used clinically to inhibit the growth of malignant cells in patients with CML and gastrointestinal stromal tumors (GISTs). Although initially considered to have minimal effects of normal hematopoiesis, recent studies show that imatinib also inhibits the growth of some nonmalignant hematopoietic cells, including monocyte/macrophages. This inhibition could not be attributed to the known activity profile of imatinib. Here, we demonstrate for the first time that imatinib targets the macrophage colony-stimulating factor (M-CSF) receptor c-fms. Phosphorylation of c-fms was inhibited by therapeutic concentrations of imatinib, and this was not due to down-regulation in c-fms expression. Imatinib was also found to inhibit M-CSF-induced proliferation of a cytokine-dependent cell line, further supporting the hypothesis that imatinib affects the growth and development of monocyte and/or macrophages through inhibition of c-fms signaling. Importantly, these results identify an additional biologic target to those already defined for imatinib. Imatinib should now be assessed for activity in diseases where c-fms activation is implicated, including breast and ovarian cancer and inflammatory conditions.
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PMID:Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. 1563 41

Yondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.
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PMID:Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. 1580

The overexpression of the colony-stimulating factor-1(CSF-1) by epithelial ovarian cancer cells enhances invasiveness and metastatic properties, contributing to the poor prognosis of the patients. It has been suggested that CSF-1 3' untranslated region containing AU-rich elements (ARE) could regulate CSF-1 posttranscriptional expression and be responsible for its aberrant abundance in such cancer cells. In this study, normal (NOSE.1) and malignant (Hey) ovarian epithelial cells were used to examine CSF-1 expression and regulation. CSF-1 overexpression in Hey cells was found to associate with increased invasiveness, motility, urokinase activity, and virulence of tumorigenicity, compared with NOSE.1 cells, which expressed little CSF-1. CSF-1 ARE was further found to serve as an mRNA decay element that correlates with down-regulation of protein translation. Moreover, such down-regulation was found more prominent in NOSE.1 than in Hey cells, suggesting differences in posttranscriptional regulation. As a variety of trans-acting factors [AU-binding protein (AUBP)] are known to modulate messenger stability through binding to such elements, we examined the protein content of both cell lines for their ability to bind the CSF-1 ARE. Our results strongly suggested the abundance of such AUBP activity in Hey cells. We isolated a 37-kDa AUBP, which was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). To summarize, our study identified GAPDH as an AUBP abundant in Hey cells, where it binds to CSF-1 ARE that imparts mRNA decay. These data suggest that GAPDH binding to CSF-1 ARE sequence prevents CSF-1 mRNA decay and subsequent down-regulation of CSF-1 protein translation, leading to CSF-1 overexpression and increased metastatic properties seen in ovarian cancer.
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PMID:Glyceraldehyde-3-phosphate dehydrogenase binds to the AU-Rich 3' untranslated region of colony-stimulating factor-1 (CSF-1) messenger RNA in human ovarian cancer cells: possible role in CSF-1 posttranscriptional regulation and tumor phenotype. 1586 72


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