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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phase I clinical trial was conducted with recombinant human tumour necrosis factor alpha (rhTNF-alpha) in 62 patients with advanced malignancy refractory to previous standard therapy. rhTNF-alpha was given as a 30 min infusion twice a day at 6 h intervals. A total of 10 different dose levels was escalated in cohorts of 6 patients ranging from 2.5 to 200 micrograms/m2 twice a day for 5 days every second week for a total of 8 weeks followed by a 4-week observation period. Major side-effects of TNF-alpha therapy, seen in almost all patients studied, were fever and chills. As dose-limiting side-effects hypotension and liver toxicity were recorded in 4 of 5 patients treated with 200 micrograms/m2 twice a day. Pharmacokinetic studies revealed a TNF-alpha serum half-life of 13 to 25 min, a dose-dependent decrease in TNF clearance, and a dose-dependent increase in the area under the time/concentration curve. No anti-TNF-alpha antibodies could be detected, except in 1 patient. Tumour response to TNF treatment was poor. Only in 3 of 57 evaluable patients was partial tumour regression observed.
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PMID:Phase I trial of recombinant human tumour necrosis factor alpha in patients with advanced malignancy. 183 17

Lymphocyte-derived, natural, glycosylated interleukin 2 (IL 2) may have different effects in vivo than the non-glycosylated recombinant IL 2 hitherto employed in clinical trials. To test this, 9 tumor patients were given 3-6 x 10(6) U/day natural IL 2 by continuous infusion for 5 days. Compared with previously published results obtained using recombinant IL 2, as far as similar tests were performed, no unexpected results were obtained with natural IL 2 in the present study. Plasma TNF-alpha levels increased considerably during therapy, IFN-gamma very slightly, whereas IL 2-stimulated secretion of either cytokine in vitro fluctuated greatly. CD16+ and CD25+ cells increased and CD45R+ cells decreased after treatment, consistent with significant lymphocyte activation in vivo. MHC-unrestricted cytotoxicity increased after treatment. The level of CD8+ cells was and remained within the normal range, although suppressive activity generated in mixed lymphocyte culture was deficient prior to therapy. Interestingly, this normalised after therapy. These results extend studies of immunological monitoring of patients receiving IL 2, based on the first trial using natural rather than recombinant IL 2.
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PMID:Clinical trial of natural human lymphocyte-derived interleukin 2 in cancer patients: effects on cytokine production and suppressor cell status. 183 86

Tumor bearing hosts and animals treated with endotoxin commonly show a decrease in the catalase activity of the liver and kidney. Since tumor necrosis factor (TNF)/cachectin may play a significant role in these conditions, we investigated its effects on the catalatic and peroxidatic activity of catalase in the liver and kidney of the rat. The activities of glucose-6-phosphate dehydrogenase and lactate dehydrogenase were measured simultaneously to monitor the pentose phosphate and glycolytic pathways, respectively. Injection i.p. of 100 micrograms/kg/day human recombinant TNF-alpha for 5 days resulted in a significant (P less than 0.01) decrease in the catalatic activity of the liver when compared to rats fed ad libitum. The decrease in four experiments ranged from 21 to 56%. A significant decrease (18%; P = 0.01) in liver catalatic and peroxidatic activity was also observed in another experiment using pair fed rats as controls. The peroxidatic activity of catalase with ethanol as hydrogen donor closely paralleled the catalatic activity. TNF treatment had no detectable effect on the catalatic or peroxidatic activity of catalase in the kidney. The activity of glucose-6-phosphate dehydrogenase increased (31-80%) significantly (P less than or equal to 0.02) in the liver and, to a lesser extent, in the kidney (5-27%, P = 0.05). Lactate dehydrogenase activity decreased (14-19%) significantly (P less than or equal to 0.05) in the liver and kidney but mainly in rats treated with TNF and additionally fasted for 24 h. Electron microscopic examination of liver sections showed that the hepatocytes of TNF-treated rats were undamaged but contained fewer and smaller peroxisomes than those of the control rats.
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PMID:Tumor necrosis factor/cachectin decreases catalase activity of rat liver. 185 14

Peripheral blood mononuclear cells (PBMC) cultured in a medium containing interleukin 2 (IL 2) develop the ability to kill fresh tumor cells. This function has been termed lymphokine activated killing (LAK). Recently, cord LAK cell activity was demonstrated to be equally as cytotoxic against similar in vitro targets as adult (peripheral) LAK cells. We investigated the future therapeutic use of LAK adoptive immunotherapy by examining LAK in vitro cytotoxicity from both cord and peripheral blood mononuclear cells against pediatric malignant tumor cell lines Y-79 (retinoblastoma). Cord LAK cells show higher levels of cytotoxicity toward Y-79 targets than do adult LAK cells. Attempts to enhance the rIL 2-induced LAK activity by addition of rIFN-gamma or PSK (krestin) were successful. Furthermore, we found that PSK has a function to enhance rIL 2-induced IFN-gamma and TNF-alpha production. These findings suggest that combined administration of cord LAK cells and PSK may account for the improvement of advanced retinoblastoma in the neonatal period.
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PMID:Effect of lymphokine-activated killer cells on human retinoblastoma cells (Y-79) in vitro: enhancement of the activity by a polysaccharide preparation, krestin. 189 89

Tumor-infiltrating lymphocytes (TIL) have been cultured from a variety of human tumors, and some melanoma TIL have demonstrated specific, MHC-restricted recognition of autologous tumor in short term lysis assays. The current study investigates cytokine release by TIL as an indicator of specific tumor recognition. We have identified two of four melanoma and one of seven breast carcinoma TIL cultures that specifically release granulocyte-macrophage-CSF, TNF-alpha, and IFN-gamma after autologous tumor stimulation. The other cultures either do not secrete cytokine or secrete cytokine in a nonspecific fashion. The amount of specific cytokine released is directly related to the number of TIL and stimulating tumor cells. Studies of TIL, from two melanoma patients, separated into CD4+ and CD8+ populations revealed that CD8+ cells were responsible for virtually all of the specific cytokine secretion, although both populations released cytokines when activated by immobilized anti-CD3 antibody. Specific cytokine release by CD8+ TIL was inhibited by anti-MHC class I mAb. Specific cytokine release was also detected from a CD4+ breast cancer TIL culture, and this was inhibited by anti-MHC class II mAb. The clinical significance of this specific mode of immune antitumor reactivity is currently under investigation.
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PMID:Specific release of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IFN-gamma by human tumor-infiltrating lymphocytes after autologous tumor stimulation. 190 60

The human monoblastoid tumor cell line U937 was induced to differentiate along the monocyte/macrophage lineage by treatment with 5 x 10(-9) M 12-O-tetradecanoyl phorbol-13-acetate (TPA). Between 2 h and 4 h following TPA-treatment U937 cells started to release significant amounts of TNF-alpha which remained detectable until 8-10 days. A significant IL-1 beta release was measured 24 h-48 h post stimulation and increased levels of IL-1 beta persisted until 20-22 days of culture. In contrast no release of either IL-1 alpha or IL-6 could be detected with 5 x 10(-9) M TPA during the whole time course of the experiments. The sequential induction of TNF-alpha and IL-1 beta appeared to be independently regulated since TNF-alpha release was not required for the onset of IL-1 beta production. Northern-blot analysis confirmed the sequential induction and the long term expression of TNF-alpha and IL-1 beta mRNAs. Western-blot analysis predominantly showed a high molecular weight IL-1 beta protein of about 35 kD. Further investigations on the regulation of cytokine production and release by TPA-differentiated U937 cells revealed that TNF-alpha and IL-1 beta synthesis was not influenced by exogenously added rhTNF-alpha or PGE2, whereas rh gamma-IFN specifically enhanced the IL-1 beta production. Thus, the regulation and intracellular processing of cytokines generated by differentiating U937 cells shows some differences when compared to mature monocytes/macrophages which may be related to the tumorigenic origin of U937 cells or to an incomplete differentiation.
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PMID:Regulation of TNF-alpha, IL-1 and IL-6 synthesis in differentiating human monoblastoid leukemic U937 cells. 190 15

Interleukin 2 (IL-2)-activated lymphocytes (lymphokine-activated killer [LAK] cells) have been shown to inhibit the formation of autologous human granulocyte-macrophage hemopoietic progenitors (granulocyte-macrophage colony-forming units, CFU-GM) in vitro. Effects of LAK cells on these progenitors may include a number of different mechanisms. LAK cells are potent cytotoxic lymphocytes capable of lysing certain normal autologous cells. They also produce cytokines known to inhibit hemopoiesis (interferon gamma [IFN-gamma] and tumor necrosis factor alpha [TNF-alpha]) or enhance it (granulocyte-macrophage colony-stimulating factor, GM-CSF). In our current study we analyzed the mechanism of suppression of autologous CFU-GM by LAK cells. Our results suggest that LAK cells are not directly cytotoxic to normal CFU-GM. We show that it is possible to abolish the hemopoiesis-inhibiting activity of LAK cells without abrogating their cytotoxicity against tumor cell lines using inhibitors of DNA synthesis, namely hydroxyurea or irradiation.
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PMID:Mechanism of suppression of normal hemopoietic activity by lymphokine-activated killer cells and their products. 190 68

The effect of short wave length ultraviolet C (UVC) light irradiation on tumor cell immunogenicity and sensitivity to natural cell-mediated cytotoxicity was studied. Two consecutive courses of UVC irradiation of 3LL Lewis lung carcinoma and MCA105 fibrosarcoma increased their immunogenicity and sensitivity to lysis by normal spleen cells. Analysis of the effector cells involved in lysis of the parental MCA105 and UV-treated MCA105UV tumor cells was performed by comparing the cytotoxic activity of normal spleen cells containing both natural killer (NK) and natural cytotoxicity (NC) cell activity (NK+, NC+) with: (a) normal spleen cells in which NC activity was neutralized by anti-tumor necrosis factor (TNF) antibodies (NK+, NC-); (b) NK-depleted or NK-deficient spleen cells (NK-, NC+); and (c) NK-depleted or -deficient spleen cells with NC activity blocked by anti-TNF antibodies (NK-, NC-). In addition, the ability of polyinosinic-polycytidylic acid or interleukin 2-stimulated spleen cells to lyse UV-treated and untreated tumor cells in the presence or absence of anti-TNF antibodies was also investigated. Lysis of MCA105 cells was shown to be mediated mostly by NC cells, since it was inhibited in the presence of anti-TNF antibodies and was not significantly affected by depletion or stimulation of NK cells. UV irradiation of MCA105 tumor cells substantially increased their sensitivity to both NK and NC effector cells. Augmentation of NK sensitivity of MCA105UV cells was associated with an increase in their lysability by large granular lymphocyte-derived cytolytic granules. UVC treatment of tumor cells also increased their sensitivity to lysis by recombinant TNF-alpha, pointing to the possible mechanism responsible for the increase in their sensitivity to NC cell-mediated cytotoxicity. Indeed, selection of MCA105UV cells for resistance to TNF led to resistance to spleen cell-mediated NC cytotoxicity. UVC irradiation did not affect internalization and degradation of TNF by MCA105UV cells but substantially increased sensitivity to TNF-induced DNA fragmentation. The results of this study indicate that UV irradiation can be a potent and stable modulator of the immunobiological properties of tumor cells.
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PMID:Increase in immunogenicity and sensitivity to natural cell-mediated cytotoxicity following in vitro exposure of MCA105 tumor cells to ultraviolet radiation. 191 41

IFN-gamma is an important mediator of cellular resistance against microbial pathogens and tumor cells due in part to its potent capacity to activate macrophages for enhanced cytotoxicity. The present study demonstrates that TNF-alpha regulates the expression of enhanced antimicrobial activity by triggering IFN-gamma primed macrophages to kill or inhibit intracellular Toxoplasma gondii. Resident mouse macrophages stimulated with rIFN-gamma at levels up to 2500 U/ml failed to display enhanced antitoxoplasmal activity when cultured in vitro under low endotoxin conditions (less than 10 pg/ml), but were triggered by addition of small amounts of LPS (0.1 ng/ml). A similar requirement for LPS as a second signal necessary to trigger antitoxoplasmal activity was observed when IFN-gamma was administered to mice in vivo. The essential nature of this triggering step allowed us to explore the role of cytokines that act as endogenous regulators of macrophage activation. rTNF-alpha, although unable to confer antitoxoplasmal activity when used alone to treat macrophages, was capable of triggering IFN-gamma-primed macrophages cultured under low endotoxin conditions. The ability of TNF-alpha to trigger IFN-gamma-primed macrophages was blocked by rabbit anti-TNF-alpha polyclonal antisera but was not affected by polymyxin B indicating that TNF-alpha triggering was not due to contamination with LPS. Collectively, these findings demonstrate that TNF-alpha performs an important regulatory role in the expression of enhanced anti-microbial activity by IFN-gamma-primed macrophages.
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PMID:Tumor necrosis factor-alpha triggers antitoxoplasmal activity of IFN-gamma primed macrophages. 191 66

Three hybridoma cell lines secreting monoclonal IgG antibodies specific for human tumor necrosis factor-binding protein I (TNF-BP I), the extracellular domain of the 60 kDa TNF receptor, were developed by fusion of spleen cells from mice immunized with TNF-BP I purified from urine. The antibodies recognize three different epitopes on TNF-BP I. Two of the antibodies were used to develop a two-site ('sandwich') enzyme immunoassay with horseradish peroxidase as the marker enzyme. The assay was able to measure TNF-BP I in serum, urine and cell culture supernatants with a sensitivity of about 200 ng/l and a precision better than 10%. TNF-BP I was detected in the serum of healthy individuals at a mean concentration of 2.1 +/- 1.0 micrograms/l (mean +/- standard deviation; range, 0.52-5.4 microgram/l, n = 42); no significant difference was seen in patients with chronic polyarthritis (2.3 +/- 0.79 micrograms/l; n = 15). Serum TNF-BP I was significantly elevated in patients with burns (6.5 +/- 1.7 micrograms/l; n = 10) and markedly increased in patients with renal failure (49 +/- 17 micrograms/l; n = 6). TNF-BP I was also detectable in urine from normal individuals (2.2 +/- 1.2 micrograms/l; range 0.78-4.3 micrograms/l; n = 16). Culture supernatants of several human tumor cell lines also contained TNF-BP I. The assay will be a useful tool to detect activation of the TNF receptor by the physiological ligands, TNF-alpha and TNF-beta, as well as transmodulation by other mediators in various pathological conditions.
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PMID:A monoclonal antibody-based enzyme immunoassay for quantitation of human tumor necrosis factor binding protein I, a soluble fragment of the 60 kDa TNF receptor, in biological fluids. 191 33


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