Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00082 (IL-2)
 29,198 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To enhance the effect of adoptive immunotherapy (AIT), we investigated the induction and characteristics of lymphokine activated killer (LAK) cells and also analyzed the combined effects of AIT with an antitumor drug (cyclophosphamide: CPA) in mice models. LAK cells were generated from C57/BL/6 (B6) spleen cells. The spleen cells were passed through a nylon wool column and cultured in RPMI-1640 medium containing 10% FCS and 2 x 10(3) units of human recombinant IL-2 (hr IL-2) for up to 14 days. During this period, the time kinetic analyses of the LAK cells' cytotoxicity and motility were performed. The cytotoxicities against Lewis Lung Carcinoma (3LL), evaluated by standard 51Cr release assay, gradually increased during the cultured period, and the motilities, determined by a modified version of the Boyden chamber method, greatly increased within the first 7 days' incubation. Based on these in vitro findings, we examined the efficacy of AIT alone or in combination with chemotherapy (CPA) in in vivo studies. AIT was performed in the following way: LAK cells were intravenously infused and rIL-2 was intraperitoneally administered for 5 consecutive days following LAK cell administration. CPA was intraperitoneally administered. The therapy protocols were as follows. There were seven experimental groups. Group I; the mice were infused with 3-day cultured LAK cells (3DLAKs) on the second day after tumor inoculation (day 2). Group II; the mice were infused with 3DLAKs on day 5. Group III; 10-day cultured LAK cells (10DLAKs) on day 2. Group IV; 10DLAKs on day 5. Group V (AIT and CPA combination); AIT (10DLAKs) was started on day 5 followed by CPA on day 10. Group VI; CPA was performed on day 5 followed by AIT (10DLAKs) on day 10. Group VII; CPA was performed on day 5 without AIT. Each group consisted on 15 mice. The therapeutic efficacies were evaluated by calculating the median survival time of each group. The results of these experiments were as follows (mean +/- SD); Group I's median survival time was 16.8 +/- 3.2 days, Group II 15.1 +/- 2.1 days, Group III 19.2 +/- 5.4 days, Group IV 16.1 +/- 4.8 days, Group V 23 +/- 6.3 days, Group VI 32 +/- 8.4 days and Group VII 22 +/- 5.1 days. These results suggested that the efficacy of AIT is closely related to the LAK cells' cytotoxicity and motility. Although AIT alone in the advanced tumor bearing host had a limited effect, combination with CPA improved it's efficacy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[A study to increase the therapeutic effects of adoptive immunotherapy in vivo. Influence on the generation of lymphokine activated killer (LAK) cells and therapeutic effects of LAK cells with anti-tumor drug (cyclophosphamide)]. 143 Jan 14

A set of alloreactive IL-2-dependent human CD4+ 45RA-w29+56- Th cell clones was divided into two groups according to their ability to respond to IL-4 by proliferation and their susceptibility to inhibition by TNF-alpha. The latter cytokine blocked proliferative responses to IL-2 of IL-4-nonresponsive clones, but did not affect proliferation of IL-4-responsive clones. In the present communication, it is demonstrated that exposure of apparently non-cytotoxic Th cells to IL-4 resulted in the dose-dependent induction of allospecific CTX in clones previously shown to be capable of responding to IL-4 by proliferation. In contrast, IL-2 induced both allospecific and MHC-unrestricted "NK-like" CTX in both IL-4 responder and nonresponder TCC. However, coculture with IL-4 in addition to IL-2 down-regulated this induction of NK-like CTX by the IL-2 (in those clones capable of responding to IL-4). Acquisition of these two types of CTX by the same TCC was additionally modulated by TNF-alpha, which also blocked the induction of NK-like CTX but had no effect on the induction of allospecific CTX by either IL-2 or IL-4. In contrast, IFN-gamma was unable to block induction of either type of CTX in this model system. These data suggest that even at the clonal level, the relative availability of a number of different up- and down-regulatory cytokines influences the outcome of an immune response. In the present model, IL-2 up-regulates specific and NK-like CTX, the latter component of which is down-regulated by TNF-alpha or IL-4, whereas IL-4 itself can up-regulate specific but not NK-like CTX.
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PMID:Modulation of IL-2- and IL-4-induced cytotoxicities in human T helper lymphocyte clones by tumor necrosis factor-alpha. 167 Sep 47

We examined immune function and changes in T cell populations over a 1-year period in a series of progressive multiple sclerosis (MS) patients treated with different regimens of cyclophosphamide/ACTH as part of the Northeast Multiple Sclerosis Treatment Group. Our studies were designed to determine the effect of different cyclophosphamide/ACTH regimens on T cell populations and functional immune assays and to determine whether immune measures could be identified to predict which patients responded favorably to treatment. Cyclophosphamide/ACTH infusions significantly decreased the proportion of peripheral blood CD4+ T cells at 2, 6 and 12 months following treatment while there was a tendency for increased CD8 expression. This was associated with significant decreases of CD4/CD8 ratios at 2, 6 and 12 months following treatment compared to pretreatment. No changes in CD3+ T cells were observed while there were increased percentages of CDw26 (Ta1) positive and IL-2 positive T cells following treatment. The only T cell populations predictive of improvement were percentages of either CD3+ or CD4+ cells where increased percentages of either these populations at 2 months following cyclophosphamide/ACTH infusions were associated with improvement at both 6 and 12 months. In terms of functional immune measures, we found that cyclophosphamide/ACTH treatment decreased the level of proliferation in the allogeneic mixed lymphocyte reaction (MLR) at 2 months and of spontaneous proliferation of mononuclear cells at 12 months following therapy. Changes in spontaneous proliferation were predictive of clinical improvement at 12 months in that subjects with improved scores on the disability status scale (DSS) had decreases in spontaneous proliferation at 12 months as compared to pretreatment, whereas those stable or worse did not change significantly. Thus, our studies have demonstrated specific alterations in immune function following immunosuppression with cyclophosphamide/ACTH and suggest that certain immune measures may be linked to a positive clinical response and thus associated with disease progression in MS.
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PMID:Immunologic effects of cyclophosphamide/ACTH in patients with chronic progressive multiple sclerosis. 167 70

A case of hepatic and splenic metastases of lung cancer infused with LAK cells and anticancer drugs from hepatic artery with total implantable port (Port-A-Cath: Pharmacia, Incorp.) was reported. A 56-year-old male was admitted to our hospital because of general fatigue, jaundice, pleural effusion and elevation of transaminase caused by hepatic and splenic metastases of lung carcinoid. Abdominal ultrasonography revealed 6 hepatic metastatic foci 10-35 mm in diameter and splenic metastases. The patient received 5 courses of MMC infusion, CPA (2 courses) and epirubicin, CDDP (3 courses), and 5 courses of LAK cells (total 1.4 x 10(10)) with IL-2 and OK-432. Eight months after initiation of treatment, jaundice and pleural effusion disappeared, transaminase returned to the normal level and the condition of the patient improved. Although the response of hepatic metastases to the treatment was NC, the size of a splenic metastasis decreased from 35 x 55 mm to 24 x 35 mm (PR).
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PMID:[Infusion of LAK cells and anticancer drugs with a total implantable port to a patient with metastatic liver and spleen tumors]. 187 42

We have evaluated the effect of Interleukin-2 [IL-2] after Cyclophosphamide (C) chemotherapy in 41 patients with metastatic cancer. IL-2 was given as a continuous infusion priming cycle 36 hours after C at 1 gm/m2 intravenously. In 39 evaluable patients, there were no complete remissions [CR], 2 partial remissions [PR], and 1 had a minor response [MR]. Stable disease for 30 days was seen in 16 patients whereas 20 progressed. The durations of partial and minor responses were brief, ranging from 1-6 months. Grade 3-4 neutropenia was seen in 41%. This was more severe than seen with IL-2 alone or IL-2 combined with lower doses of C. The marrow suppression was due to the chemotherapy. This combination of IL-2 and C appears to be reasonably well tolerated by patients, but toxicity is greater and the response rate is no better than results achieved by IL-2 alone. Responses of 26 patients with renal cancer appear to be inferior to our historical data using IL-2/LAK cells without C. Immune monitoring demonstrated changes expected with C chemotherapy (i.e., a non-selective decline in immune function). C induced no further differences in IL-2 induced changes in immune function.
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PMID:Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial. 191 Jun 23

Tumor necrosis factor (TNF) is a well-described and characterized cytokine which can be elicited in the intact animal by endotoxin. This factor produces necrosis of subcutaneous tumors in the classic model: Meth A sarcoma in the Balb C mouse. It has been shown to be cytostatic or cytotoxic for a variety of human cancer cell lines, as well as to have effects against both mouse tumors and human cancers carried in the nude mouse. TNF is most likely produced by the macrophage. TNF has been cloned, and has been shown to have a molecular weight of 17,000 and to contain approximately 157 acids in its active form. The genes responsible for TNF are contained on chromosome 6 in man, which also contains genes of the major histocompatibility complex. Although there are similarities to lymphotoxin, which is produced by mitogen-stimulated lymphocytes, and to interleukin-1 (IL-1), which is also produced by macrophages, TNF has distinctive differences, primarily in its antiproliferative effects. TNF is also allied with the effects of cachexia and has been shown to be similar to, if not exactly the same as, cachectin. Although it appears that effects of TNF require expression of receptors to facilitate binding to the cell, there is not a quantitative relationship between receptors and the sensitivity. TNF cytotoxic effects appeared to be amplified by pretreatment of cells with chemotherapeutic agents such as Actinomycin D, Adriamycin, and Cytoxan as well as to have synergistic effects with gamma interferon, alpha interferon, and IL-2. Although initial phase I and phase II studies of TNF in man have shown the expected toxicity, there have been minimal antitumor effects. It is anticipated that with more sophisticated studies, perhaps combining TNF with either biological or chemotherapeutic agents, TNF's true role in cancer therapy may well unfold.
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PMID:Tumor necrosis factors. 268 30

Allogeneic bone marrow transplantation (BMT) is associated with the cumulative toxicity of high dose chemotherapy and/or radiation therapy regimens currently in use, with acute and chronic graft vs host disease (GVHD), as well as with the consequences of delayed immunological reconstitution due to slow maturation of the immune system and drugs currently used for prevention of GVHD. Although GVHD may be overcome by T-cell depletion it leads to an increased incidence of graft rejection and relapse of the original malignancy. These too represent major problems. Autologous BMT results in high relapse rates due to lack of immune-mediated allogeneic interactions of grafted cells against tumor cells of the host. In view of the fact that experiments in animal models of human disease suggest that antileukemic effects of allogeneic marrow grafts may be partially independent of GVHD, new approaches for amplification of antitumor effects of autologous and allogeneic cells by cytokines and by lymphokine-activated cells are discussed. Evidence for antileukemia effects of IL-2 therapy in animals is presented. Beneficial effects of several cytokines in autologous and allogeneic BMT are suggested by significant facilitation of immunological and hematopoietic reconstitution following transplantation of bone marrow cells treated in vitro with cytokines (including ASTA-Z-purged marrow) and following in vivo administration of cytokines in conjunction with BMT. Overall, in view of several innovative biological interventions, it seems that significant progress in autologous and allogeneic BMT may be underway; the concept yet to be established is that successful and less risky BMT may be accomplished by replacing aggressive chemoradiotherapy regimens with sophisticated immunomanipulations and biological response modifying agents.
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PMID:Current problems and future goals in clinical bone marrow transplantation. 306 32

Low density fractions of Percoll density gradient centrifugation of peripheral mononuclear cells contained the majority of large granular lymphocytes (LGL). LGL were used for 5-hr 51Cr release cytotoxic assay against autologous tumor cells in 20 patients with hematological malignancies (9AML, 4ALL and 7NHL). Mean % cytotoxicity (% CTX) was 6.0%, and the addition of IFN-beta and IL-2 in the medium induced the significant increase of % CTX to 15.0% and 26.1%, respectively. When LGL cultured in medium containing IFN-beta and IL-2 were assessed for cytotoxicity daily for 8 days, the enhancement of % CTX by IFN-beta was declined in a few days, while the enhancement by IL-2 was sustained for more than 8 days. The pretreatment of LGL with anti Leu-11 (CD16) plus complement abrogated the enhancing effect by IFN-beta or IL-2, but not with anti Leu-1 (CD5) plus complement. When this treatment was done on day 8 of IL-2 cocultivation, anti Leu-11 plus complement suppressed cytotoxicity significantly, and anti Leu-1 plus complement also induced mild suppression. The phenotypic characteristics of cells revealed the significant increase of anti Leu-19+ cells in IL-2 stimulated day 8 cells. High density fractions of Percoll gradient contained mostly T lymphocytes and showed no cytotoxicity against autologous tumor cells. However, cocultivation with IL-2 for 8 days induced the cytotoxicity, associated with increased number of anti Leu-19+ cells. These results suggested that IL-2 induced cytotoxic activity against autologous tumor cells might be related to the increase of anti Leu-19+ cells.
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PMID:[The effect of IL-2 and IFN-beta on autologous tumor cell kill by Percoll separated LGL fractions]. 315 15

Adoptive immunotherapy with LAK-cells in conjunction with high-dose IL-2 has recently been introduced in the treatment of patients with advanced cancer. This therapeutic modality has thus far proved to be of limited efficacy, severe toxicity and entails complicated logistics. Our present study is aimed at establishing a model system to test for increasing efficacy and reducing toxicity by using AIT cojointly with chemotherapy. Mice implanted i.v. or i.p. with weakly immunogenic tumors (M109 lung carcinoma, MCA-105 sarcoma) were treated 7 to 20 days after tumor inoculation with or without CTX, with and without recombinant human IL-2, and with and without syngeneic/allogeneic LAK-cells. Whereas IL-2 or IL-2 + LAK-cells without CTX was largely ineffective, and CTX alone cured 0 to 20% of the animals with an i.p. tumor and only slightly reduced pulmonary tumor mass, the combination of CTX + IL-2 cured 50 to 80% of the mice bearing i.p. tumors and reduced pulmonary tumor growth by greater than or equal to 80%. The combination of CTX + IL-2 + LAK-cells proved no more beneficial than CTX + IL-2 without LAK-cells. Also relevant were the observations that murine LAK-cells are transiently sensitive to moderate doses of CTX (greater than or equal to 100 mg/kg body weight) and X-irradiation (greater than equal to 400 rad), and that administration of IL-2 by the i.v. or i.p. route variously affects LAK-cell activation in different tissues and eradication of growths localized at different sites. With the regimens used, no signs of toxicity were detected. It is proposed that instillation of IL-2 (and perhaps of additional immunostimulating cytokines as well) as an adjunct to chemotherapy (or chemoradiotherapy), each given at a subtoxic dose, is both safe and effective in the treatment of metastatic advanced tumors, and that the additional administration of LAK-cells may not be required.
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PMID:Therapy of advanced solid tumors in mice using chemotherapy in combination with interleukin-2 with and without lymphokine-activated killer cells. 326 51

We have studied the anti-tumor response to cyclophosphamide (CTX) in DBA/2 mice transplanted s.c. with 4 tumors exhibiting different responses to IL-2: ESb lymphoma and Friend leukemia cells (non-responsive or poorly responsive, respectively), p11-R-Eb and Eb lymphoma cells (both highly responsive to IL-2). CTX injections on days 7, 14 and 21 resulted in a significant anti-tumor response in mice transplanted s.c. with Friend leukemia cells or ESb cells, whereas no anti-tumor effect was observed in mice injected with Eb or p11-R-Eb cells. All 4 tumor cell lines were equally sensitive to the cytotoxic effects of mafosfamide, an in vitro active analogue of CTX. To define the host mechanisms responsible for the lack of an anti-tumor effect of CTX in mice transplanted with IL-2-responsive tumors, we studied several aspects of the spontaneous or IL-2-induced anti-tumor response in mice transplanted with p11-R-Eb cells. Injection of monoclonal antibodies (MAbs) to IFN-gamma completely abolished the anti-tumor effects of IL-2. Using a Winn assay, clear-cut anti-tumor activity was found in spleen cells from mice transplanted with the IL-2-responsive tumors. This activity was abolished by CTX, which also abrogated the anti-tumor response to IL-2 in mice injected with p11-R-Eb cells. Our results indicate an inverse correlation between sensitivity to IL-2 and response to CTX and emphasize the importance of initial host-tumor interaction in determining the type of response to IL-2 or CTX.
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PMID:Correlation between the sensitivity or resistance to IL-2 and the response to cyclophosphamide of 4 tumors transplantable in the same murine host. 762 94


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