Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sustained release or high levels of interleukin-1 (IL-1) and/or tumor necrosis factor (TNF), as observed after endotoxin challenge, can produce a variety of toxicities. Naturally occurring inhibitors to IL-1 and TNF, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor forms, have been detected. These proteins may function to buffer or limit the effects of these cytokines as part of a regulatory network. As part of a clinical trial of recombinant human interleukin-1 beta (rhIL-1 beta), serial plasma samples were obtained from 6 patients with metastatic melanoma treated with 30-min infusions of rhIL-1 beta for 5 consecutive days. The presence of circulating IL-1 receptor antagonist and soluble TNF binding proteins (TNF-R55-BP and TNF-R75-BP) were assessed. A maximum 86-fold increase for IL-1ra, a 7-8-fold increase for TNF-R55-BP, and a 2-3-fold increase for TNF-R75-BP were seen 2-4 h, 1 h, and 4 h, respectively, after rhIL-1 beta infusion. On each day of the treatment, the secretion of IL-1ra and release of TNF-R55-BP was observed, but there was no accumulation above baseline value for IL-1ra before each of the 5 daily infusions. Although there was a steady decrease of the 6-h postinfusion plasma levels for IL-1ra and TNF-R55-BP over the 5 treatment days, no increase of clinical side effects was noted. Two patients had measurable levels of TNF-alpha, but no correlation to TNF-binding proteins was observed. Our data show that early after rhIL-1 beta infusion the induction of IL-1ra secretion, as well as TNF-binding protein release, is observed.
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PMID:Interleukin-1 beta induces interleukin-1 receptor antagonist and tumor necrosis factor binding protein in humans. 839 34

Tumour necrosis factor-alpha (TNFalpha) is a cytokine with a variety of biological activities, including an effect on tumour growth. The soluble TNF receptor TNF-R55 (sTNF-R55) inhibits TNFalpha functioning. Serum values of TNFalpha and TNF-R55 have been observed in patients with different cancers. To determine the serum values of TNFalpha and its soluble receptors and to investigate the prognostic value of sTNF-R55, we studied the sera of 68 patients with metastatic melanoma, 109 patients with no recurrent disease after surgical removal of melanoma, and 69 healthy controls. At least four different monoclonal antibodies against human TNFalpha and human TNF-R55, respectively, were prepared to obtain sensitive and reliable sandwich enzyme-linked immunosorbent assays. We found that in patients with metastatic melanoma the serum values of sTNF-R55 were significantly higher (2.41 ng/ml; range 0.02 23.0 ng/ml; P < 0.05) than in the melanoma patients without recurrence (0.54 ng/ml; range 0.02-6.25 ng/ml) and healthy controls (0.5 ng/ml; range 0.02 5.0 ng/ml). The sTNF-R55 concentrations increased as the disease progressed. Patients with metastatic melanoma also had significantly higher concentrations of TNFalpha (3.34 ng/ml; range 0.03-30.0 ng/ml; P<0.05) than patients without recurrence (1.24 ng/ml; range 0.02 23.0 ng/ml). Patients with metastatic melanoma, a high sTNF-R55 concentration, a low TNFalpha concentration and a low TNF:sTNF-R55 ratio had the worst prognosis. Low values of sTNF-R55 (<0.6 ng/ml) were associated with favourable response to chemotherapy (P = 0.007). According to our findings, patients with metastatic melanoma have higher values of sTNF-R55 than the controls and melanoma patients without recurrence. sTNF-R55 values higher than 0.6 ng/ml and a TNF:sTNF-R55 ratio lower than 1.5 are unfavourable prognostic factors for response to chemotherapy.
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PMID:Serum values of tumour necrosis factor-alpha and of soluble tumour necrosis factor-R55 in melanoma patients. 1089 Mar 79

The main difficulty in the successful treatment of metastatic melanoma is that this type of cancer is known to be resistant to chemotherapy. Chemotherapy remains the treatment of choice, and dacarbazine (DTIC) is the best standard treatment. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor, and antimetastatic properties. The objective of this study was to evaluate the signaling pathways involved in melanoma cell death after treatment with DM-1 compared to the standard agent for melanoma treatment, DTIC. Cell death was evaluated by flow cytometry for annexin V and iodide propide, cleaved caspase 8, and TNF-R1 expression. Hoechst 33342 staining was evaluated by fluorescent microscopy; lipid peroxidation and cell viability (MTT) were evaluated by colorimetric assays. The antiproliferative effects of the drugs were evaluated by flow cytometry for cyclin D1 and Ki67 expression. Mice bearing B16F10 melanoma were treated with DTIC, DM-1, or both therapies. DM-1 induced significant apoptosis as indicated by the presence of cleaved caspase 8 and an increase in TNF-R1 expression in melanoma cells. Furthermore, DM-1 had antiproliferative effects in this the same cell line. DTIC caused cell death primarily by necrosis, and a smaller melanoma cell population underwent apoptosis. DTIC induced oxidative stress and several physiological changes in normal melanocytes, whereas DM-1 did not significantly affect the normal cells. DM-1 antitumor therapy in vivo showed tumor burden decrease with DM-1 monotherapy or in combination with DTIC, besides survival rate increase. Altogether, these data confirm DM-1 as a chemotherapeutic agent with effective tumor control properties and a lower incidence of side effects in normal cells compared to DTIC.
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PMID:The curcumin analog DM-1 induces apoptotic cell death in melanoma. 2335 72

Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the "rapid expansion protocol" (REP) were not designed to enhance the generation of optimal effector-memory CD8(+) T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8(+) effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8(+) T cells, on the yield, phenotype, and functional activity of expanded CD8(+) T cells during the REP. We found that CD8(+) TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8(+) T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8(+) post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8(+) T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients.
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PMID:Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy. 2356 68