Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A genetically engineered fusion protein consisting of a human/mouse chimeric anti-ganglioside GD2 antibody (ch14.18) and recombinant human interleukin 2 (rhIL-2) was tested for its ability to target rhIL-2 to tumor sites and stimulate immune effector cells sufficiently to achieve effective tumor cell lysis in vivo. The ch14.18-IL-2 fusion protein proved more effective than equivalent doses of rhIL-2 in suppressing dissemination and growth of human neuroblastoma in an experimental hepatic metastases model of scid (severe combined immunodeficiency) mice reconstituted with human lymphokine-activated killer cells. The ch14.18-IL-2 fusion protein was also more proficient than equivalent doses of rhIL-2 in prolonging the life-span of these animals. This recombinant antibody-cytokine fusion protein may prove useful for future treatment of GD2-expressing human tumors in an adjuvant setting.
 ...
PMID:A recombinant antibody-interleukin 2 fusion protein suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice. 793 18

Since the immune system plays an important role in the rejection of tumours, current tumour therapy includes immunostimulation. This can be done by interleukin 2 (IL-2), which activates T and killer cells and induces lysis of the tumour. Because the intravenous application of IL-2 may have serious side effects, we treated two patients with peritumoral injections in a pilot study. Both patients suffered from multiple cutaneous metastases of melanoma. A total of 31 and 39 x 10(6) IU recombinant IL-2 (Proleukin) respectively was injected in increasing concentrations in one metastasis of each patient. Histologically, almost complete necrosis of the tumour was induced. In comparison with the control specimen, the T-cell-rich infiltrate increased intra- and, in particular, peritumorally. While the ratio of helper to suppressor T cells remained unchanged, the proportions of NK cells, monocytes/macrophages and IL-2-receptor-bearing cells increased. This reaction was restricted to treated metastases. No clinical side effects or laboratory changes were registered apart from local erythema and swelling.
 ...
PMID:[Peritumoral administered IL-2-induced tumor regression in melanoma. Pilot study]. 796 Jul 53

The mechanisms underlying the impaired immune response frequently observed in cancer patients are poorly understood. Recently, a decreased expression of the signal-transducing CD3 zeta chains has been shown to occur in patients with colorectal or renal-cell carcinoma. Here, we have investigated the expression of the zeta molecule on lymphocytes from patients with advanced cancers including renal-cell carcinoma (n = 21), hepatic colorectal carcinoma metastases (n = 6), head-and-neck squamous-cell carcinoma (n = 7) or miscellaneous tumors (n = 7), using flow cytometry analysis of PBMCs with monoclonal antibody specific for the cytoplasmic domain of the zeta chain. The same analysis was also performed with patients undergoing IL-2 therapy (from 5 days up to 3 months i.v. or s.c.). PBMCs from patients (n = 41) showed a significant decrease in expression of the zeta chains as compared to the levels found in lymphocytes from healthy controls (n = 15), which was not reversed by IL-2 administration. Together, these results suggest that an alteration in the expression of the zeta-chain-transducing element in PBMCs may be a common cause of progressive immunosuppression in advanced cancer patients and that IL-2 is not sufficient to reverse this situation in vivo.
 ...
PMID:The decreased expression of CD3 zeta chains in cancer patients is not reversed by IL-2 administration. 798 13

Human NK cells can be separated into two functionally distinct subpopulations based on the ability to rapidly respond to IL-2 by adherence to solid surfaces. To determine functions of the NK cell subsets in solid tumor tissues, adherent (A) and nonadherent (NA) NK cells were evaluated for their ability to infiltrate multicellular tumor spheroids in vitro, to kill carcinoma (CA) cell targets in these spheroids, and to mediate antitumor activity in vivo. A-NK cells were less cytolytic than NA-NK cells against CA targets in single cell suspensions or in monolayers. However, A-NK cells showed a significantly better ability than NA-NK cells to infiltrate tumor tissues and kill tumor cells in spheroids of human squamous cell CA of the head and neck or breast CA. Perilesional delivery of human A-NK cells and IL-2 resulted in regression of established human squamous cell carcinoma of the head and neck tumors growing subcutaneously in immunosuppressed nude mice. Similarly, in a xenograft model of human gastric CA metastatic to liver of nude mice, a single intrasplenic injection of A-NK cells in combination with i.p. infusions of IL-2 significantly reduced the number of established hepatic metastases (p < 0.007) and prolonged survival of the mice (p < 0.003). In contrast, NA-NK cells were ineffective in either of the in vivo xenograft tumor models. These findings demonstrate that A-NK cells represent a biologically unique and important subset of NK cells that, in contrast to the rest of NK cells, function as effector cells in solid tumor tissues and, consequently, have a great antitumor therapeutic potential.
 ...
PMID:Antitumor activities of subsets of human IL-2-activated natural killer cells in solid tissues. 799 47

The antitumor efficacy of IL-2 is limited to renal cancer and melanoma. Several cytokines have been associated with IL-2 in an attempt to improve its activity, without, however, any clear benefit. Recent experimental and clinical studies have suggested the possibility to manipulate the host biological response by immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On the bases of these considerations, we have designed a neuroimmunotherapeutic protocol with low-dose IL-2 subcutaneous therapy (3 million IU/day for 6 days/week for 4 weeks) plus MLT (40 mg/day orally, starting 7 days before IL-2) in advanced solid neoplasms other than renal cancer and melanoma, which are generally resistant to IL-2 alone. The study included 82 patients, 72 of whom showed distant organ metastases. Tumor histotypes were, as follows: non-small cell lung cancer: 19; hepatocarcinoma: 16; colon cancer: 15; gastric cancer: 11; cancer of pancreas: 11; breast cancer: 6; miscellaneous: 4. Objective tumor regression were achieved in 17/82 (21%) patients, consisting of CR in 4 (liver: 2; pancreas: 1; stomach: 1) and PR in 13 (lung: 4; liver: 4; stomach: 2; pancreas: 1; breast: 1; colon: 1). The median duration of response was 8+ months. A stabilization of disease was obtained in 30 patients, while the other 35 patients progressed. The lack of progression was associated with a significantly higher increase in lymphocyte and eosinophil mean number and with a significantly lower increase in neopterin mean levels. The treatment was well tolerated in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cancer immunotherapy with low-dose interleukin-2 subcutaneous administration: potential efficacy in most solid tumor histotypes by a concomitant treatment with the pineal hormone melatonin. 802 99

Metastatic or locally advanced renal cell carcinoma is refractory to chemotherapy and radiotherapy. Surgical treatment is the mainstay of treatment in these cases. The concept of surgical treatment of renal cell carcinoma was discussed by classifying the procedures into four categories: 1) radical nephrectomy; 2) nephron sparing surgery, such as partial nephrectomy and enucleation for small renal cancer detected incidentally by ultrasonography and CT; 3) extended surgery for cases having IVC tumor thrombus or with invasion of neighboring organs; and 4) surgery for metastatic disease. New therapies such as LAK, alpha-Interferon and IL-2 do not improve the 20% response rate. Gene therapy using appropriate vectors for introduction of IL-2. Interferon or GM-CSF genes to renal cancer cells is still at an experimental stage.
 ...
PMID:[Surgical treatment for renal cell carcinoma]. 806 Jan 29

Histamine type-2 receptor antagonists (H-2RA) have been used chronically to prevent dyspepsia in cancer patients subjected to immunotherapy with chronic indomethacin (Indo) and intermittent IL-2 in our cancer centre. We tested the effects of these agents during immunotherapy of C3H/HeJ mice transplanted s.c. with 5 x 10(5) C3L5 mammary adenocarcinoma cells. Tumor-transplanted mice were divided into groups receiving: (1) Indo (14 micrograms/ml); (2) H-2RA, i.e. (a) ranitidine at 28.6 micrograms/ml (Ran-lo) or 143 micrograms/ml (Ran-hi), or (b) famotidine (Fam) at 4.3 micrograms/ml, or (c) cimetidine (Cim) at 107 micrograms/ml, all in the drinking water on days 5-24; (3) IL-2 (1.5 x 10(3) Cetus U i.p. every 8 h on days 10-14 and 20-24); (4) combinations of H-2RA + Indo; or (5) combinations of H-2RA + Indo + IL-2. Animals were killed on day 24 for examination of primary s.c. tumor growth, secondary lung metastasis and splenocyte cytotoxicity against YAC-1 lymphoma cells (51Cr release assay). Results revealed: (1) primary tumor growth was reduced in mice treated with Fam + Indo, Indo + IL-2 and any of the H-2RA + Indo + IL-2 (no difference observed within the last two groups); (2) lung metastases decreased in mice treated with IL-2 alone, Indo + IL-2, and Indo + IL-2 + Ran-hi; (3) splenic cytotoxicity was suppressed in tumor-bearing controls, with partial restoration seen in Ran (both doses), Ran-lo + Indo, Ran-lo + Indo + IL-2, and Cim + Indo + IL-2 treated groups. Nearly complete restoration was seen in Cim, Cim + Indo, Indo + IL-2, Ran-hi + Indo + IL-2, and Fam + Indo + IL-2 groups. Thus, addition of H-2RA did not alter the overall therapeutic efficacy of the standard Indo + IL-2 tumor immunotherapy.
Clin Exp Metastasis 1993 May
PMID:Effects of histamine type-2 receptor antagonists on indomethacin and IL-2 immunotherapy of metastasis. 809 42

The number of IL-2-activated natural killer (A-NK) cells reaching the tumor site in vivo may be crucial for their anti-tumor effect following adoptive immunotherapy. We investigated in a syngeneic rat model the infiltration of established lung metastases by adoptively transferred A-NK cells. The Wag rat colon carcinoma CC531 was injected via a tail vein to induce pulmonary metastases. Syngeneic A-NK cells were labeled with the fluorescent dye rhodamine (TRITC) and next injected via a tail vein in rats bearing day-12 lung tumors. The number of A-NK cells in tumor and in normal tissue per rat was counted in sections after administration of A-NK cells. At all time points tested, a significant linear relationship between the cross-section area of the tumor and the number of infiltrating cells was observed, but small tumor areas became fully infiltrated earlier than larger areas. At 24 hr after injection, approximately 10% of the injected cells were found in the tumor tissue and the average A-NK-cell-to-tumor-cell ratio was estimated to be 1:3. A-NK cells were found in the liver too, although the number of cells per mm2 tissue was low compared with the pulmonary tumor tissue. Very low numbers of A-NK cells were found in kidney, adrenal gland, spleen, and blood. We conclude that, in this syngeneic rat model, adoptively transferred A-NK cells are able to find and specifically infiltrate pulmonary metastases in a time-dependent fashion.
 ...
PMID:The infiltration of experimentally induced lung metastases of colon carcinoma CC531 by adoptively transferred interleukin-2-activated natural killer cells in Wag rats. 811 94

In this study, we describe the origin and characterization of a new metastatic tumor cell line (p11-R-Eb) obtained after i.p. passages of the nonmetastatic Eb lymphoma cells into DBA/2 mice. The p11-R-Eb cells exhibited the same morphology and in vitro growth properties and chromosome markers as the original Eb cells. FACS analysis of the p11-R-Eb cells also revealed a close similarity to the Eb cells. Moreover, the p11-R-Eb cells were specifically killed by anti-Eb cytotoxic lymphocytes. In spite of all these characteristics of the Eb line, p11-R-Eb cells metastasized to the liver when injected i.v. or s.c. in DBA/2 mice. Peritumoral interleukin (IL)-2 treatment resulted in a potent antitumor response in DBA/2 mice transplanted s.c. with p11-R-Eb cells. In contrast, the same IL-2 regimen did not significantly increase the survival time of mice transplanted with the highly metastatic ESb cell line. Combined IL-1/IL-2 treatments of established p11-R-Eb tumors resulted in a synergistic antitumor effect and in tumor regression in 70% of the injected mice. Similarly, combined peritumoral treatment with IL-1 and interferon-alpha/beta, which were poorly effective or ineffective as single cytokine therapy, resulted in a marked antitumor effect, and 30% of the mice were cured. Spleen cells from IL-1/IL-2-treated p11-R-Eb-cell-injected mice showed a marked antitumor activity when assayed in a Winn assay with homologous tumor cells. This antitumor activity was eliminated by preincubation of spleen cells with antibodies to CD4 and complement and markedly inhibited by anti-asialo GM1 antibodies. P11-R-Eb cells represent, therefore, a new tumor model which may be useful for investigating the relevant mechanisms which need to be activated to achieve a potent antitumor response to cytokine therapy in the DBA/2 mouse host.
Invasion Metastasis 1993
PMID:Isolation and characterization of a metastatic Eb-like tumor variant highly responsive to interleukin (IL)-2 and to combination cytokine therapy with IL-2/IL-1 beta and IL-1 beta/interferon-alpha/beta. 811 75

Lymph nodes draining a progressively growing tumor contain T-cells which can be activated sequentially by anti-CD3 and IL-2 to differentiate into tumor-specific effector cells. In this study, long-term cultured T-cell lines were established from activated MCA 106 tumor-draining lymph node cells by periodic stimulation with irradiated tumor cells in the presence of low concentrations of IL-2 (< or = 60 International units/ml). Such long-term cultured cell lines maintained therapeutic effects when transferred to tumor-bearing mice. Although the initial anti-CD3/IL-2-activated T-cells displayed a broad distribution of T-cell antigen receptor beta chain variable region (V beta) usages, long-term cultured cells were dominated by T-cells expressing a few V beta elements. Of six cell lines, only three V beta phenotypes (V beta 5, 11, 13) were identified, and individual cell lines frequently expressed a single V beta gene product. Despite restricted V beta expression, each cell line mediated tumor-specific reactivity in adoptive immunotherapy. Many T-cell clones were isolated from long-term cell lines. Three V beta 13 T-cell clones demonstrated specific in vivo antitumor effects, whereas two V beta 11 and two V beta 5 clones revealed a significant degree of cross-reactivity against the antigenically distinct MCA 205 tumor. Although the initial anti-CD3/IL-2-activated cells lacked demonstrable cytotoxic reactivity, T-cell clones derived from them exhibited cytotoxic effects to the MCA 106 tumor cells. The specificity of the cytotoxicity mediated by each clone reflected its in vivo antitumor effects. Furthermore, studies of in vivo localization of cloned T-cells demonstrated tumor-specific infiltration of the 5A2 (V beta 13) clone to the MCA 106 tumor metastases, whereas clone 9H6 (V beta 5) revealed some accumulation in the MCA 205 tumor. Again, the in vivo antitumor effects of the 9H6 clone correlated with its in vivo infiltration into the specific MCA 106 and the nonspecific MCA 205 metastases. Taken together, the long-term culture of anti-CD3/IL-2-activated tumor-draining lymph node cells resulted in selective expansion of a few T-cells as evidenced by the limited T-cell receptor V beta expression. Our results also demonstrated that systemically administered antitumor T-cell clones gained access and accumulated at metastatic tumor sites, and the degree of infiltration correlated with the specificity of the in vivo antitumor effect as well as the in vitro cytotoxic activity.
 ...
PMID:Characteristics and in vivo homing of long-term T-cell lines and clones derived from tumor-draining lymph nodes. 816 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>