Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-infiltrating lymphocytes (TILs) have potent antitumor effects in murine models of advanced disease. Although these cells are 50-100 times more potent than lymphokine-activated killer cells against micrometastases, their antitumor benefits are virtually nonexistent against large tumor burdens unless cyclophosphamide is added to the immunotherapy regimen. In an effort to determine the effects of cyclophosphamide on TILs obtained from tumor-bearing animals, we harvested tumors from animals having received either 0, 50, or 100 mg/kg cyclophosphamide intravenously and investigated the expansion, cytotoxicity, and phenotypic expression of these TILs co-cultured in vitro with recombinant interleukin-2. TILs obtained from animals given cyclophosphamide, demonstrated a greater fold expansion than TILs obtained from normal animals (mean fold expansion on day 59 of culture: 85, 400, and 150 for TILs obtained from animals given 0, 50, and 100 mg/kg cyclophosphamide, n = 3 consecutive experiments). In addition, these TILs demonstrated enhanced cytotoxicity compared to controls [effector to target ratio 4:1, day 16 TILs, % lysis: 24, 35, and 45%, cyclophosphamide 0, 50, and 100 mg/kg, respectively, against the MCA-102 sarcoma, natural killer (NK) insensitive tumor; 29, 38, and 56% against the YAC-1 lymphoma, NK sensitive tumor]. Similar results were seen with day 34 and day 59 TILs. When phenotypic analysis was performed, TILs obtained from animals given cyclophosphamide consistently demonstrated a greater percent expression of the Thy1.2 and Lyt-2 antigens up to day 59 of culture when the experiments were terminated. The NK cell marker 49H.8 was expressed on the majority of TILs and its expression did not change with respect to the cyclophosphamide concentration. The increase in TIL number and cytotoxicity seen with cyclophosphamide given intravenously before tumor harvest could have important ramifications for human immunotherapy with TILs.
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PMID:Tumor-infiltrating lymphocytes cultured in recombinant interleukin-2: enhancement of growth, cytotoxicity, and phenotypic expression of cytotoxic T-cell antigens by cyclophosphamide given intravenously prior to tumor harvest. 278 92

Interleukin-2 (IL-2) has been evaluated as a therapeutic agent in a number of metastatic tumor systems. We hypothesized that administration of IL-2 might be more effective as adjuvant therapy in the presence of a greatly diminished tumor burden after tumor excision. In this BALB/c methylcholanthrene-induced sarcoma model, excision of 0.3 to 0.4 gm tumors results in local recurrence rates of 50% to 70%. Administration of human recombinant IL-2 at a dose of 50,000 units three times daily for 5 days to animals with established tumors resulted in 100% mortality. IL-2 administration started at the time of tumor implantation had no effect on tumor growth. Mice receiving adjuvant IL-2 at 50,000 units per dose after surgery had prolonged survival compared with controls (79% vs. 32%, p = 0.007); addition of concanavalin A-activated lymphocytes to IL-2 therapy did not enhance survival over that with IL-2 alone. Therapy with lower doses of adjuvant IL-2 on the same treatment schedule resulted in improved survival at doses as low as 5000 units (86% vs. 51% for controls, p = 0.003). Although the exact mechanism of this therapeutic effect has not been determined, IL-2 may act by a variety of mechanisms, including a decrease in the immunosuppressive effects of anesthesia and surgery, the generation of endogenous IL-2-activated effector cells, and the augmentation of efflux of circulating effector cells from peripheral blood into the site of surgically induced inflammation.
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PMID:Efficacy of adjuvant interleukin-2 after excision of BALB/c fibrosarcomas. 278 15

Twenty patients with supratentorial, intracerebral lesions defined by computed tomographic scan or magnetic resonance imaging were treated by surgery and adoptive immunotherapy with lymphokine-activated killer (LAK) cells and recombinant Interleukin-2 (rIL-2, Cetus). Seventeen patients had glioblastoma, two had high-grade oligodendroglioma, and one patient had two metastatic sarcoma lesions. LAK cells were produced from blood mononuclear cells (MNC) obtained by 2 to 3 leukapheresis procedures and cultured (2.5 x 10(6) MNC/ml) 3 to 5 days with 1000 units rIL-2/ml. Although LAK cells could be produced from MNC of all patients, those taking steroids or with a low Karnofsky functional status generated, on average, suboptimal LAK cell activity. Age, sex, and serum anticonvulsant levels do not seem to influence a patient's ability to produce LAK cells in vitro. For therapy, cultured MNC (1-15 x 10(9] containing LAK cells were suspended in saline containing 10(6) units rIL-2 and injected into tissue surrounding the tumor cavity during craniotomy. For 3 days after their operations, patients received 10(6) units rIL-2 into the tumor cavity through an Ommaya reservoir. The treatment protocol was tolerated well by all patients, although they all experienced some degree of headache, fever, or lethargy that cleared within a few days of the last rIL-2 injection. When computed tomographic (CT) scans were obtained soon after treatment, areas of low density suggested a greater-than-normal extent of edema around the operative site. At the present time, CT scans indicate that the tumors of seven patients have recurred with an average disease-free interval of 25 +/- 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intralesional infusion of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) for the treatment of patients with malignant brain tumor. 285 Nov 16

We have been able to detect soluble interleukin-2 receptors (IL-2R) in pretreatment sera from 80 patients with undifferentiated lymphoma (predominantly Burkitt's lymphoma) and lymphoblastic lymphoma. The demonstration of IL-2R in lymphoma-derived cell lines by immunoprecipitation and direct staining indicates that IL-2R is synthesized by the tumor cells. Comparisons were made with two other subject groups: 42 sarcoma patients and 17 normal individuals. The distribution of soluble IL-2R values for lymphoma patients (geometric mean, 1,132 U/mL) was significantly greater than that of sarcoma patients (geometric mean, 332 U/mL; P = .0001) or normal individuals (geometric mean, 238 U/mL; P = .0001). Patients with undifferentiated lymphoma stages B, C, and D had significantly higher soluble IL-2R values (geometric mean, 1,648 U/mL) than stages A and AR (geometric mean, 706 U/mL; P = .0001) or lymphoblastic lymphoma (geometric mean, 826 U/mL; P = .0002). Within the lymphoma group, the soluble IL-2R level was found to be the most significant prognostic indicator of disease-free interval and survival when compared with other previously recognized factors such as histology, stage, bone marrow involvement at presentation, lactic dehydrogenase (LDH), uric acid (UA), and age. No factor was significantly associated with response to therapy, ie, the initial achievement of complete remission (CR) status, although small numbers of patients with a partial response limit interpretation. Soluble IL-2R levels were measured serially in two patients and were found to be elevated at presentation or relapse and to decrease to normal levels during periods of disease remission. IL-2R appears to reflect tumor burden and may prove to be a useful and specific marker for lymphoid tumors.
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PMID:Soluble interleukin-2 receptor levels in patients with undifferentiated and lymphoblastic lymphomas: correlation with survival. 311 36

Tumor necrosis factor and interleukin-2 each in recombinant form have antitumor activity against established tumors if used in high enough dosages. The problem associated with such high dosages is the high degree of toxicity and expense encountered. Therefore, this study was undertaken to look at the antitumor efficacy of these two lymphokines when used together at dosages well below the toxic levels. Our results using recombinant human interleukin-2 (IL-2) and recombinant human tumor necrosis factor (TNF) against established methylcholanthrene-induced fibrosarcoma (MCA sarcoma) pulmonary metastases showed that TNF and IL-2 therapy at low nontoxic dosages alone did not produce significant tumor regression, but when combined at the same dosage synergize producing significant antitumor effects in mice induced with MCA sarcoma. This was also evident from histopathological examination of the lungs where the maximum tumor reduction along with the maximum lymphocytic infiltration into tumor was seen when TNF and IL-2 were combined. In this tumor regression, inherent immunity of the treated mice was needed, since in those mice in which we induced immunosuppression by using radiation, tumor regression was not seen when TNF and IL-2 therapy was combined in the doses efficacious in immunocompetent mice. Tumor regression is also dependent on the sequence of administration of IL-2 and TNF, since when IL-2 was administered before TNF, the tumor regression was more significant than when TNF was administered before IL-2 or when both were administered simultaneously to mice with established pulmonary tumors. Therefore the synergistic effect of IL-2 and TNF could be used as an efficacious but inexpensive and nontoxic alternative to therapy with lymphokine activated killer (LAK) cells + IL-2.
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PMID:Therapy of disseminated NK-resistant tumor by the synergistic effects of recombinant interleukin-2 and tumor necrosis factor. 325 5

The antitumor activity of combination therapy with recombinant tumor necrosis-alpha (rhTNF-alpha) and recombinant interleukin-2 (rhIL-2) was assessed against established immunogenic (MCA-106) and nonimmunogenic (MCA-102) sarcomas at both s.c. and visceral (hepatic) sites. C57BL/6 (B6) mice were treated with a single i.v. dose of rhTNF-alpha (2, 4, 6, or 8 micrograms) followed by rhIL-2 (25,000 U) i.p. thrice daily for 5 consecutive days. Synergistic effects as measured by regression of tumor, prolongation of survival, and improved cure rates were found using the combination of rhTNF-alpha plus rhIL-2 compared to rhTNF-alpha alone or rhIL-2 alone in the treatment of the immunogenic sarcoma MCA-106. No significant antitumor effects were observed against the nonimmunogenic MCA-102 sarcoma. These findings were similar for both s.c. and large single hepatic tumor models. The effect of the timing of rhIL-2 injections in relation to rhTNF-alpha administration (concurrent, 2, 4, or 6 days post single rhTNF-alpha dose) was also evaluated. Substantial tumor regression and increased survival times were seen in mice with s.c. tumors when rhIL-2 therapy was delayed as much as 48 h after rhTNF-alpha administration. No antitumor response was noted with the combination compared to rhTNF-alpha alone when rhIL-2 was delayed for greater than 4 days. No increase in lethal toxicity during treatment course of the combination of rhTNF-alpha and rhIL-2 was noted at any schedule compared to single agent rhTNF-alpha therapy. A possible role of rhTNF-alpha in regulation of IL-2-dependent antitumor activity in vivo is discussed.
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PMID:Synergistic antitumor effects of immunotherapy with recombinant interleukin-2 and recombinant tumor necrosis factor-alpha. 326 Jan 30

Previous studies have indicated the efficacy of adoptive immunotherapy utilizing recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells in the treatment of advanced neoplastic disease. However, this therapeutic approach is associated with considerable toxicity, primarily due to the systemic administration of rIL-2. The present study was undertaken to determine the efficacy of a newly developed water-soluble glucan, when administered in combination with LAK cells, in the therapy of experimental hepatic metastases. Mice were challenged subcutaneously (1 X 10(4) cells) with reticulum cell sarcoma M5076 on day 0. Therapy was initiated on day 15, when a palpable primary tumor mass and hepatic micrometastases were evident, and continued at 3-day intervals up to day 54. Sarcoma-bearing mice received glucan (250 mg/kg) intravenously, either alone or in combination with LAK cells (1 X 10(7)/mouse). Control mice received 5% (wt/vol) dextrose in water. Glucan-LAK cell therapy significantly suppressed primary tumor growth, inhibited the progression of hepatic metastases and prolonged survival in sarcoma-bearing mice. Splenocytes, incubated with rIL-2 for 72 h, exhibited significant natural killer (NK) cell activity and were cytotoxic to sarcoma cells in vitro. Glucan-LAK cell administration resulted in significant increases in splenic NK cell activity and Kupffer cell-mediated tumoricidal activity. In addition, bone marrow proliferation was enhanced following the co-administration of glucan and LAK cells. Due to its nontoxic nature and immunostimulating properties, soluble glucan may prove to be an attractive biological response modifying agent for utilization in adoptive immunotherapy of advanced neoplastic disease.
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PMID:Soluble glucan and lymphokine-activated killer (LAK) cells in the therapy of experimental hepatic metastases. 328 99

The studies described in this paper showed that the combination of i.v.-transferred lymphokine-activated killer (LAK) cells and i.p. injections of recombinant interleukin-2 (RIL-2) was highly effective in vivo in reducing established pulmonary metastases of natural killer cell-resistant, MCA-105 sarcoma and B16 melanoma in mice. A 3-day in vitro incubation of normal C57BL/6 splenocytes in medium containing pure RIL-2 generated LAK cells that, when combined with RIL-2, reduced the mean number of established pulmonary micrometastases of the B16 melanoma and of the MCA-105 sarcoma from 179 and 140, respectively (in groups treated with Hanks' balanced salt solution alone), to 12 (P = 0.01) and 6 (P = 0.01), respectively. This combined immunotherapy also consistently resulted in significant prolongation of survival in mice with established, 3-day or 10-day pulmonary metastases of the MCA-105 sarcoma. Mice autopsied at time of death revealed a massive involvement of tumor in the lungs and liver in the group receiving Hanks' balanced salt solution alone compared to a small number of residual large lung or liver metastases in the group receiving LAK cells plus RIL-2. Experiments were designed to test whether variants existed in the original tumor cell inoculum that were resistant to killing by LAK cells and thus could account for the metastases that "escaped" the combined immunotherapy of LAK cells plus RIL-2 in vivo. Metastases of the MCA-105 sarcoma that escaped the combined therapy of LAK cells plus RIL-2 were dissected from the organs of mice upon autopsy and directly tested for susceptibility in vitro to lysis by LAK cells in 4-h and 18-h 51Cr release assays. Target cells derived from the metastases were lysed to an equivalent extent as those prepared from a fresh MCA-105 sarcoma that was growing s.c. In addition, successful reduction of pulmonary metastases established by the i.v. infusion of MCA-105 sarcoma cells obtained from metastases that escaped a prior round of therapy with LAK cells and RIL-2 could be achieved in vivo by the combined immunotherapy as well as by high doses of RIL-2 alone. Culture adapted, natural killer cell-resistant B16 melanoma cells surviving two successive treatments with LAK cells in vitro remained as susceptible to LAK cell lysis as untreated B16 melanoma cells in 18-h 51Cr release assays.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo: survival benefit and mechanisms of tumor escape in mice undergoing immunotherapy. 348 31

Recombinant human interleukin-2 (rIL-2, courtesy of Cetus Corporation, Emeryville, CA, U.S.A.) is highly effective in eradicating syngeneic tumor when administered to C57BL/6 mice implanted with a nonimmunogenic, rapidly growing clone of B16 melanoma, or an immunogenic methylcholanthrene-induced sarcoma, 1-3 days, before beginning treatment at 5 X 10(4) U/injection daily for 5 days, and then on alternate days for 4 weeks. Low-dose cyclophosphamide (CY, 50 mg/kg), injected intraperitoneally (i.p.) 4 times at weekly intervals, greatly facilitated tumor eradication in rIL-2-treated mice. Most early subcutaneous (s.c.) tumors were cured by combining CY i.p. with repeated perilesional s.c. injections of rIL-2, i.e, 100% cure for 1-day and 87-91% for 3-day melanomas. When rIL-2 was administered without CY, the cure rate was 64% for 1-day and 67% for 3-day melanomas. This cure rate indicated a synergism between rIL-2 and CY, since CY alone did not affect tumor incidence. CY was therefore administered in all subsequent experiments. Treatment with rIL-2, localized to the site of the melanoma or sarcoma, was most effective, although systemic (i.p.) administration achieved results regardless of tumor site. When either tumor was implanted s.c. and rIL-2 treatment was also given s.c. locally, beginning 1-3 days later, 87-100% of the mice were cured, compared with 35-50% cured when rIL-2 was administered i.p., and 0% cured in excipient buffer-injected controls. Conversely, with i.p. treatment of i.p. tumors, 60-83% of the mice were tumor-free on day 50, as compared with only 17% tumor-free if treatment was s.c. These in vivo model systems should prove useful in helping establish protocols for human therapy.
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PMID:Successful immunotherapy of mouse melanoma and sarcoma with recombinant interleukin-2 and cyclophosphamide. 349 May 44

Traditional methods for toxicological assessment have implicated the immune system as a frequent target organ of toxic insult following chronic exposure to certain environmental chemicals, radiation or therapeutic drugs (xenobiotics). Immunotoxicity is expressed as autoimmunity, chemical hypersensitivity or immunosuppression. A tiered approach for characterizing chemical and drug-induced immunomodulation has been developed and validated in laboratory animals. Polycyclic aromatic hydrocarbons (PAH) have been studied because of their ubiquitous presence in the environment and carcinogenic potential. Since immunosuppression induced by PAH carcinogens has been implicated as an epigenetic mechanism in the outgrowth of initiated cells, this tiered approach was used to characterize the mechanism of PAH immunosuppressive capacity. Previously, studies in this laboratory have demonstrated that subchronic exposure of B6C3F1 mice to PAH carcinogens suppresses both humoral immunity (HI) and cell-mediated immunity (CMI), concurrently with decreased resistance to tumor challenge. The potent carcinogenic PAH, 7,12-dimethylbenz[a]anthracene (DMBA) was subchronically administered subcutaneously at 5, 50, or 100 micrograms/g of body weight. Natural killer (NK) cell tumor cytolysis, generation of cytotoxic T-cells (CTL), and lymphoproliferation to mitogens and allogeneic splenocytes in mixed leukocyte cultures (MLC) were quantitated 3-5 days after exposure to assess CMI. Mitogen and alloantigen-induced proliferation (MLC) of splenocytes was suppressed up to 90%. CTL and NK tumor cytolysis of radiolabelled target cells were similarly depressed up to 88 and 82%, respectively. Impairment of MLC or CTL responses correlated with increased susceptibility to challenge with PYB6 sarcoma cells. HI was measured by quantitating the number of antibody (IgM) plaque-forming cells (PFC) produced in response to T-cell dependent antigen challenge (sheep erythrocytes) and was similarly suppressed up to 95%. To understand the mechanism of PAH-induced immunotoxicity, splenocytes from DMBA-exposed mice were sensitized to alloantigens in the presence of interleukin-2 (IL-2) because there were indications that T-helper cell function was suppressed. In these preliminary studies, CTL suppression could be completely restored by the addition of the T-cell growth supporting lymphokine (IL-2) during the inductive phase of CTL generation, suggesting that DMBA exposure directly or indirectly induced deficits in T-helper cell function.
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PMID:Mechanisms of dimethylbenzanthracene-induced immunotoxicity. 392 65


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