Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated 14 consecutive patients with leptomeningeal metastasis prospectively, using both T1-weighted (T1W) gadolinium-DTPA-enhanced MR (Gd-MR) and contrast-enhanced CT (CE-CT). Thirteen had positive CSF cytology; the remaining patient had an atypical CSF lymphocytosis and primary CNS lymphoma. The patients (8M/6F) ranged in age from 8 to 70 years (median, 42 years). Tumor histology included 3 systemic and 2 primary CNS lymphomas, 3 breast carcinomas, 2 leukemias, 1 malignant schwannoma, 1 small cell lung cancer, 1 prostate cancer, and 1 melanoma. Both imaging methods demonstrated parenchymal volume loss equally well in all patients. Gd-MR revealed abnormal enhancement of meninges or parenchyma in 10 patients, including all 5 patients with positive CE-CT. Neither technique revealed any foci of abnormal enhancement in 4 patients. Gd-MR was superior to CE-CT in demonstrating and quantifying enhancing subarachnoid and parenchymal nodules in 6 patients and in demonstrating sulcal, dural, cisternal, tentorial, and ependymal enhancement. Our findings indicate that T1W Gd-MR is the preferred imaging modality in leptomeningeal metastasis and suggest that CE-CT is unnecessary.
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PMID:Leptomeningeal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. 231 84

Prostate cancer selectively metastasises to skeletal sites, where it normally produces osteoblastic lesions. This study investigated whether haematopoietic growth factors known to be present in the bone environment could be involved in the survival and proliferation of prostate skeletal metastases. To evaluate this hypothesis we investigated the effects of recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF), recombinant granulocyte colony-stimulating factor (rG-CSF), recombinant erythropoietin (rEPO) and recombinant interleukin-3 (rIL-3) on the growth of 3 human prostate cancer cell lines. Two hormone-insensitive cell lines, PC-3 and DU145, were significantly stimulated by rGM-CSF and rEPO in serum-free medium but their growth was unaffected by incubation with rIL-3 or rG-CSF. A hormone-sensitive cell line, LNCaP, was stimulated only by rGM-CSF. To investigate further the involvement of GM-CSF in prostate cancer, the presence of GM-CSF protein in the 3 prostate cancer cell lines was examined by immunohistochemistry, and analysis of cell line conditioned media was carried out by ELISA and Western blotting. These techniques demonstrated that GM-CSF-like material was produced by both DU145 and PC-3 cells but not by LNCaP. The results from ELISA found that media conditioned by DU145 and PC-3 cells contained 1.7 and 2.5 pg GM-CSF/micrograms protein, respectively, whereas no GM-CSF was detectable in the LNCaP conditioned media. Our results were also confirmed by Western blot analysis demonstrating one single band for DU145 and PC-3 conditioned media which co-migrated along with the standard rGM-CSF band. No bands were associated with the LNCaP conditioned media. The presence of GM-CSF gene transcripts in DU145 and PC-3 cells was established by reverse transcription and polymerase chain reaction of total RNA.
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PMID:Production and response of human prostate cancer cell lines to granulocyte macrophage-colony stimulating factor. 792 24

Two patients successfully treated for prostatic cancer developed a progressive neurologic syndrome beginning with loss of voluntary horizontal eye movements followed by severe, persistent muscle spasms of the face, jaw, and pharynx. Both had mild gait unsteadiness, and one exhibited facial and abdominal myoclonus. Extensive diagnostic studies, including MRIs of the brainstem (with and without contrast), were normal. CSF examination showed mild pleocytosis and elevated IgG. Quantitative eye movement recordings documented selective involvement of voluntary horizontal saccades with sparing of horizontal slow eye movements. Neither patient had antineuronal antibodies in the blood. Postmortem examination revealed perivascular chronic inflammatory cells and microglial infiltration of the pons and medulla. One patient also had perivascular infiltrates in both mesial temporal lobes. Neuronal loss was localized to the pontine tegmentum, the medullary sensory nuclei, and the cerebellum. Brainstem motor nuclei were preserved. The clinical and pathologic findings suggest an autoimmune process (probably paraneoplastic) with selective damage to a subpopulation of brainstem neurons critical for horizontal eye movements and recurrent inhibition of bulbar nuclei.
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PMID:Novel brainstem syndrome associated with prostate carcinoma. 825 62

The class I IgG receptor (Fc gamma RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 x humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 x Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1-15 mg/m2), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/ myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3-6 month's duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m2 given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with prostate cancer, and colorectal cancer patients, all of whom have failed standard therapy. At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118-11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon gamma (IFN gamma). These trials have been open-label, progressive dose-escalation (0.35-135 mg/m2) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. (ABSTRACT TRUNCATED)
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PMID:Clinical experience with CD64-directed immunotherapy. An overview. 943 76

One hundred and one donors who had received filgrastim (rhG-CSF) for the purpose of donating either granulocytes or peripheral blood stem cells (PBSC) for their relatives more than 3 years ago were contacted. All donors had received daily rhG-CSF at a median dose of 16 microg/kg/day (range 3-16) for a median of 6 days (range 3-15 days). All collection procedures were completed and short-term side-effects of rhG-CSF were mild in the majority of the donors. At a median time interval of 43.13 months (range 35-73), the donors were contacted to assess whether adverse effects related to rhG-CSF administration had occurred. Prior to rhG-CSF two donors had cancer, one had a myocardial infarction, one was hepatitis C virus positive, one had a history of sinusitis, one had Graves' disease and two had arterial hypertension. None worsened with the rhG-CSF administration but the donor with a history of infarction had an episode of angina following apheresis, and the donor with Graves' disease had a stroke 15 months after rhG-CSF. Two pregnancies occurred after the rhG-CSF administration and one donor was 2-3 weeks pregnant during rhG-CSF treatment. Three pregnancies resulted in two normal births and one in a spontaneous abortion of a pregnancy which occurred more than 2 years following rhG-CSF. In the time following rhG-CSF administration two donors developed cancer (breast and prostate cancer) at a follow-up of 70 and 11 months, respectively. One donor developed lymphadenopathy 38 months after the rhG-CSF, which spontaneously resolved. Blood counts were obtained in 70 donors at a median follow up of 40.4 months (range 16.8-70.8). Hematocrit was 43% (median, range 36.8-48), white blood cells were 5.7 x 109/l (median, range 3-14), granulocytes 3.71 x 109/l (median, range 1. 47-10.36), lymphocytes 1.67 x 109/l (median, range 0.90-3.96), monocytes 0.46 x 109/l (median, range 0.07-0.87) and platelet counts were 193.0 x 109/l (median, range 175.0-240.0). This study indicates that short-term administration of rhG-CSF to normal donors for the purpose of mobilizing the PBSC or granulocytes appears safe and without any obvious adverse effects more than 3 years after the donation. Bone Marrow Transplantation (2000) 25, 85-89.
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PMID:Three to six year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor. 1065 20

We attempted to induce therapeutic immunity against prostate-derived tissues in patients suffering from progressive hormone-refractory metastatic prostate carcinoma. Thirteen patients were treated with two infusions, 1 month apart, of autologous dendritic cells (APC8015) preexposed ex vivo to PA2024, a fusion protein consisting of human granulocyte/macrophage-colony stimulating factor (GM-CSF) and human prostatic acid phosphatase (PAP). The infusions were followed by three s.c. monthly doses of PA2024 without cells. Three groups of patients each received PA2024 at 0.3, 0.6, or 1.0 mg/injection. All Ps were two-sided. Treatment was well tolerated. After infusions of APC8015, patients experienced only mild (grade 1-2) short-lived fever and/or chills, myalgia, pain, and fatigue. One patient developed grade 3 fatigue. Four patients developed mild local reactions to s.c. PA2024. Twelve patients were evaluable for response to treatment. Circulating prostate-specific antigen levels dropped in three patients. T cells, drawn from patients after infusions of APC8015, but not before, could be stimulated in vitro by GM-CSF (P = 0.0004) and PAP (P = 0.0001), demonstrating broken immune tolerance against these two normal proteins. Injections of PA2024 did not influence the reactivity of T cells against PAP and GM-CSF. However, antibodies to GM-CSF and, to a much lesser extent, to PAP reached maximum titers only after two or even three injections of PA2024, showing that directly injected PA2024 was involved in stimulation of humoral immunity. Dendritic cells exposed to antigen ex vivo can induce antigen-specific cellular immunity in prostate cancer patients, warranting further studies of this mode of immunotherapy.
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PMID:Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. 1087 66

Reported paraneoplastic neurological syndromes (PNS) are rare disabling neurological diseases with supposed autoimmune pathogenesis. The aims of this study were to evaluate frequency, clinical course and therapeutic response in the cohort of PNS positive patients (n=10) in the Czech Republic for the first time. Second, we determined the presence and distribution of oligoclonal IgG bands (OB IgG) in PNS and compared the clinical and laboratory features of OB IgG positive and negative patients. A total of 2355 suspicious serum and/or CSF samples were screened by immunofluorescence and immunohistochemistry with definite confirmation by Western blot. OB IgG were detected by isoelectric focusing and immunoenzymatic staining and clinical status was scored according to modified Rankin scale (RS). Four patients had anti-Yo antibody, ovarian cancer and the score in range (2-5) on RS. Five patients had anti-Hu antibody, small cell lung cancer (SCLC), prostate cancer and the score between 1-4 grade on RS. One patient with SCLC and anti-Ri antibody had grade 2. Five of 10 patients with PNS had positive OB IgG and average value 4.2 on RS comparing with negative OB IgG patients with average value 2.6. Finally, we add well-defined cohort of PNS patients to emerging European profile of PNS and conclude that the presence of OB IgG in PNS seems to reflect enhanced immune response with more severe neurological damage and clinical course.
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PMID:Paraneoplastic neurological syndromes - patients' cohort profile in the Czech Republic. 1149 21

Transcription factor nuclear factor kappaB (NF-kappaB) controls gene expression of a number of genes, including cytokines such as interleukin-6 (IL-6), granulocyte-macrophage (GM)-CSF, and interleukin-8 (IL-8). IL-6 is known to play important roles in the growth of prostate cancer cells, activation of androgen receptor, and prostate-specific protein expression. NF-kappaB is activated by extracellular signals such as proinflammatory cytokines, chemotherapeutic reagents, and radiation. Here we demonstrate that cisplatin (CDDP) and etoposide (VP-16) induce nuclear translocation of NF-kappaB in prostate cancer cell lines, followed by secretion of IL-6. We also demonstrated that the growth of hormone-independent prostate cancer cell lines can be inhibited by the anti-NF-kappaB reagent N-acetyl-L-cysteine (NAC). These observations indicate that NF-kappaB can be a target of new adjuvant therapy against hormone refractory prostate cancer.
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PMID:N-acetyl-L-cysteine enhances chemotherapeutic effect on prostate cancer cells. 1194 26

Colony-stimulating factor-1 receptor (CSF-1R) is the major regulator of macrophage development and is associated with epithelial cancers of the breast and ovary. Immunohistochemistry analysis of murine prostate development demonstrated epithelial expression of CSF-1R during the protrusion of prostatic buds from the urogenital sinus, during the prepubertal and androgen-driven proliferative expansion and branching of the gland, with a decline in older animals. Models of murine prostate cancer showed CSF-1R expression in areas of carcinoma- and tumor-associated macrophages. Several human prostate cancer cell lines and primary cultures of human prostate epithelial cells had low but detectable levels of CSF-1R. Human prostatectomy samples showed low or undetectable levels of receptor in normal glands or benign prostatic hypertrophy specimens. Staining was strongest in areas of prostatic intraepithelial neoplasia or carcinoma of Gleason histological grade 3 or 4. The activated form of the receptor reactive with antibodies specific for phosphotyrosine modified peptide sequences was observed in samples of metastatic prostate cancer. Immunohistochemistry showed strong expression of CSF-1R by macrophage lineage cells, including villous macrophages and the syncytiotrophoblast layer of placenta, Kupper cells in the liver, and histiocytes infiltrating near prostate cancers. These observations correlate CSF-1R expression with changes in the growth and development of the normal and neoplastic prostate.
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PMID:Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression. 1238 83

Prostate-specific antigen (PSA) is a serine protease secreted at low levels by normal luminal epithelial cells of the prostate and in significantly higher levels by prostate cancer cells. Therefore, PSA is a potential target for various immunotherapeutical approaches against prostate cancer. DNA vaccination has been investigated as immunotherapy for infectious diseases in patients and for specific treatment of cancer in certain animal models. In animal studies, we have demonstrated that vaccination with plasmid vector pVAX/PSA results in PSA-specific cellular response and protection against tumour challenge. The purpose of the trial was to evaluate the safety, feasibility and biological efficacy of pVAX/PSA vaccine in the clinic. A phase I trial of pVAX/PSA, together with cytokine granulocyte/macrophage-colony stimulating factor (GM-CSF) (Molgramostim) and IL-2 (Aldesleukin) as vaccine adjuvants, was carried out in patients with hormone-refractory prostate cancer. To evaluate the biologically active dose, the vaccine was administered during five cycles in doses of 100, 300 and 900 microg, with three patients in each cohort. Eight patients were evaluable. A PSA-specific cellular immune response, measured by IFN-gamma production against recombinant PSA protein, and a rise in anti-PSA IgG were detected in two of three patients after vaccination in the highest dose cohort. A decrease in the slope of PSA was observed in the two patients exhibiting IFN-gamma production to PSA. No adverse effects (WHO grade >2) were observed in any dose cohort. We demonstrate that DNA vaccination with a PSA-coding plasmid vector, given with GM-CSF and IL-2 to patients with prostate cancer, is safe and in doses of 900 microg the vaccine can induce cellular and humoral immune responses against PSA protein.
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PMID:A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer. 1528 Sep 30


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