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

In this study the efficacy of treatment of two cyclo-oxygenase inhibitors, ibuprofen (Ibu) and indomethacin (Indo), are compared in the immunotherapy of metastasis designed to reverse prostaglandin E2 (PGE2)-mediated inactivation of interleukin-2 (IL-2)-dependent host killer cell lineages. These agents were tested either alone for the prevention of metastasis or in combination with IL-2 for the eradication of established metastasis. C3H/HeN mice were placed on chronic oral Ibu (CIbT; 200 and 600 micrograms/ml of water) or Indo (CIT; 10 micrograms/ml) 5 days after s.c. transplantation of 5 x 10(5) metastatic C3L5 mammary carcinoma for the prevention of spontaneous lung metastases. They showed intolerance to Indo at a dosage of 14 micrograms/ml, which was well tolerated by other mouse strains in previous studies, but tolerated the Ibu dosages used. Control and treated mice were killed on day 30 to score metastatic lung colonies, to evaluate killer activity in splenocytes against natural killer (NK)-sensitive YAC-1 lymphoma or NK-resistant C3L5 adenocarcinoma and 8911 lymphoma targets, and to phenotype the surface markers of killer cells. CIbT and CIT alone at the above dosage significantly reduced the number of lung colonies, retarded local tumor growth and restored NK activity of splenic killer cells expressing AGM-1+, Thy-1-, Lyt-2- phenotype. To treat established lung metastasis, mice bearing 15-day C3L5 transplants were given CIbT or CIT alone or in combination with two 4-day rounds (days 20-23, 31-34) of IL-2 (15,000 Cetus units, i.p. every 8 h) and were killed on day 35 to score lung colonies and characterize splenic killer cells. CIbT or CIT alone reduced the number of spontaneous lung metastases and restored anti-YAC-1 killer function of splenocytes with NK-like phenotype (AGM-1+, Thy-1-, Lyt-2-); some anti-C3L5 killer function was also generated in the high dose Ibu group and the killer cell showed AGM-1+, Thy-1+ and Lyt-2+ phenotype. Combined therapies with CIbT or CIT plus IL-2 were more effective in reducing metastases and promoting killer cell function, the best results being achieved with high dose Ibu+IL-2. All killer cells expressed AGM-1 and Thy-1. In addition, C3L5 killer cells also expressed Lyt-2, suggesting T-cell stimulation. PGE2 synthesis in the host was inhibited by at least 50% in mice subjected to CIbT or CIT.(ABSTRACT TRUNCATED AT 400 WORDS)
Clin Exp Metastasis 1992 Jul
PMID:Immunotherapy of mammary adenocarcinoma metastases in C3H/HeN mice with chronic administration of cyclo-oxygenase inhibitors alone or in combination with IL-2. 161 32

The dynamics of lymphoid cell subpopulations in bronchoalveolar lavage fluid (BALF) and the systemic lymphoid organs of mice after intravenous injection of B16 melanoma cells were examined with a fluorescence-activated cell sorter. The lymphoid cell subpopulations of BALF and mediastinal lymph nodes showed significant changes in numbers and proportions, while those of other lymphoid organs including inguinal lymph nodes, thymus and spleen, showed little change. In week 1, the cells with a Thy-1.2+, Lyt-1+, L3T4-, Lyt-2- phenotype and asialo-Gm1+ cells in BALF significantly increased and L3T4+ cells slightly increased in number. By week 3, the numbers of Lyt-2+ cells in BALF markedly increased in number (by about 90 times) compared with controls. The number of Thy-1.2+ cells in mediastinal lymph nodes also increased significantly by week 3. Mice that had been pretreated with an immunosuppressive dose of cyclophosphamide were also inoculated intravenously with B16 melanoma cells. In these mice, a significantly increased number of pleural tumors developed and the number of Thy-1.2+ cells in BALF was markedly reduced from week 1 to 3. The results indicate that L3T4 and Lyt-2 double negative T-cells and natural killer (NK) cells may be generated and/or mobilized to the lung in an early phase of experimental metastasis of B16 melanoma cells and that at a later stage, when multiple metastases develop, T-cells with a Lyt-2+ phenotype markedly increase, probably as an expression of a host reaction against proliferating metastatic tumor cells.
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PMID:In vivo dynamics of pulmonary lymphoid cell subpopulations generated against pulmonary metastasis: evaluation by bronchoalveolar lavage fluid. 169 54

Tumor infiltrating lymphocytes (TILs) are derived from solid tumors by culturing single cell suspensions of the tumors in low dose interleukin-2 (IL-2) and intermittent tumor stimulation. We have investigated the survival of TILs after intravenous injection into tumor-bearing mice. Using several murine transplantable sarcomas, we examined the in vivo survival of TILs derived from B6.PL Thy 1a/CY mice (Thy-1.1), which were used to treat established experimental metastases in C57BL/6N (Thy-1.2) mice. Donor and host lymphoid cells could be clearly distinguished by fluorescence-activated cell sorting. We found that TILs or TILs + IL-2 could extend the survival of and, in some instances, cure established experimental hepatic and pulmonary metastases. Donor TILs could be recovered from treated animals at all time points tested; in mice cured of pulmonary metastases donor TILs could be detected as late as 119 days after intravenous injection even in the absence of exogenous IL-2. The administration of a relatively low dose of IL-2 in vivo to mice receiving TILs increased the number of donor TILs recovered from the lungs of cured animals 5-10-fold at all time points but did not change the period of time during which donor TILs could be detected in vivo. Additionally, TILs could be recovered from animals cured of established metastases and such cells retained their antitumor activity in vivo. Finally, when mice cured of pulmonary metastases by TILs or TILs + IL-2 were rechallenged with tumor, donor TILs specifically accumulated at the site of tumor rechallenge up to 4 months after adoptive transfer of TILs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adoptively transferred tumor-infiltrating lymphocytes can cure established metastatic tumor in mice and persist long-term in vivo as functional memory T lymphocytes. 176 72

Tumor-infiltrating lymphocytes (TILs) are host T cells that can be grown from fresh murine and human tumors using interleukin-2 (IL-2) in bulk cultures. These activated T cells have been shown to have significant antitumor activity both in vitro and in vivo. A technique is described for the separation of Thy-1.2-positive TILs from fresh murine tumors using antibody-coated magnetic beads, permitting the examination of growth conditions for these cells. TILs with increased therapeutic efficacy are obtained from the immunogenic MCA 38 and MCA 105 tumors when culture conditions employing low levels of IL-2 (10 vs. 1,000 U/ml) and irradiated autologous tumor restimulation are used. TILs grown under these conditions can mediate a 93% reduction of 3-day-old established pulmonary metastases when as few as 2.5 x 10(5) cells are adoptively transferred with systemic IL-2. These culture conditions are utilized to grow TILs from the nonimmunogenic MCA 102 tumor for which bulk TIL culture methods are unsuccessful. MCA 102 TILs grown in this fashion demonstrate in vivo therapeutic efficacy against established autologous pulmonary metastases.
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PMID:An improved method for growing murine tumor-infiltrating lymphocytes with in vivo antitumor activity. 197 2

The adoptive transfer of tumor-infiltrating lymphocytes (TILs) in conjunction with interleukin-2 (IL-2) administration can mediate a reduction in established pulmonary and hepatic metastases of a variety of murine tumors as well as in patients with metastatic melanoma. To characterize further the fate of adoptively transferred TILs, the uptake of the thymidine analog 5-[125I]iodo-2-deoxyuridine ([125I]UdR) into the DNA of dividing cells was used to study the in vivo proliferation and migration patterns of transferred TILs in C57BL/6N mice. Animals received 500 rad of total body irradiation prior to cell transfer to separate incorporation of radiolabel into endogenous lymphoid cells from that into transferred TILs. Mice were subsequently treated with i.v. injections of TILs or no cells followed by i.p. injections of Hanks' balanced salt solution or IL-2. At various time points, mice received [125I]UdR, and 20 h later tissues were removed and counted on a gamma analyzer. A proliferation index (PI) was calculated by dividing the mean cpm of organs of experimentally treated mice by the mean cpm of organs of control mice. Animals receiving TILs alone demonstrated small increases in [125I]UdR in the lungs, liver, and spleen of saline-treated controls (PI = 1.4, 1.6, and 1.7, respectively, on day 4), while animals treated with 50,000 U of IL-2 alone showed greater increases in the lungs, liver, kidneys, and spleen (PI = 3.9, 6.1, 3.3, and 15.8). Mice receiving TILs plus IL-2 demonstrated the highest levels of radiolabel incorporation in the same organs (PI = 10.5, 19.4, 10.2, and 22.4). Over a period of 10 days, TIL plus IL-2 treated animals continued to incorporate significantly greater amounts of [125I]UdR for as long as high-dose IL-2 was administered. Animals treated with TILs demonstrated increased incorporation of radiolabel with increasing doses of IL-2. Injection of irradiated TILs did not result in an increased uptake of [125I]UdR into these tissues, thus confirming that TIL proliferation is responsible for the radiolabel uptake in animals receiving TILs alone or TILs plus IL-2. Additionally, fluorescein-labeled anti-Thy-1.1 antibody identified proliferating TILs derived from congenic B6.PL Thy 1a/CY (Thy-1.1) animals in the lungs, spleen, and liver of recipient C57BL/6N (Thy 1.2) mice. In summary, we have demonstrated that adoptively transferred TILs distribute widely after i.v. injection and can proliferate in various tissues especially under the influence of exogenous IL-2.
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PMID:In vivo proliferation of adoptively transferred tumor-infiltrating lymphocytes in mice. 204 92

We have shown that macrophage-derived prostaglandin (PG)E2 inactivates all interleukin 2 (IL-2) dependent killer cell lineages in the tumor-bearing host, so that chronic indomethacin therapy (CIT) combined with multiple rounds of IL-2 can cure experimental and spontaneous metastases of a variety of murine tumors. We tested the efficacy of this therapy on experimental human melanoma metastasis in nude mice and characterized the killer cells generated in situ. BALB/c nude mice were injected i.v. with 2 x 10(6) human lung-metastasizing line P52, MeWo melanoma cells. After 5 weeks, when lung nodules were well established, mice received vehicles alone (control) or were given (a) CIT (14 micrograms/ml in drinking water); (b) three rounds of IL-2, 25,000 Cetus U, 8 hourly i.p. (days 40-44, 50-54, 60-64); (c) CIT + three rounds of IL-2; (d) CIT + four rounds of IL-2 (round 4 on days 70-74); and (e) CIT + five rounds of IL-2 (round 5 on days 80-84). Control and experimental mice were killed on day 71 to score lung colonies and evaluate killer activity in splenic and lung lymphocytes and macrophages against murine YAC-1 lymphoma and B16F10 melanoma, human P52 melanoma, K562 erythroleukemia, and Raji lymphoma targets. Killer cells for P52 were phenotyped for Thy-1, Lyt-2, and asialo-GM-1 markers by ab + C'-mediated deletion of killer function. Mice in all groups were also kept for survival. CIT alone improved splenic NK activity but marginally reduced the lung colony counts or prolonged the survival time. Three rounds of IL-2 alone reduced the median colony counts by 50% and prolonged the survival by 2 weeks, but resulted in no long-term, disease-free survival, in spite of significant activation of LAK cells with Thy-1-, Lyt-2-, AGM-1+ phenotype in the spleen. CIT + 3 rounds of IL-2 reduced the median colony counts from 40 to 0 and improved the survival from a median of 66 (control) to 120 days (40% surviving 260 + days). CIT + four or five rounds of IL-2 caused long-term (260 + days) survival of 80% mice, most surviving 400 + days. The combination therapy activated killer lymphocytes (Thy-1-, Lyt-2-, AGM-1+) and, to a smaller extent, macrophages (AGM-1 +/-) in the spleen and the lungs, showing a high cytocidal ability for all the targets.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cure of human melanoma lung metastases in nude mice with chronic indomethacin therapy combined with multiple rounds of IL-2: characteristics of killer cells generated in situ. 209 Jan 99

We have previously demonstrated that depletion of CD8+ T-cells by the use of a monoclonal anti-Lyt-2.2 antibody abolishes the curative effectiveness of low-dose melphalan (L-phenylalanine mustard; L-PAM) therapy for BALB/c mice bearing a large (greater than or equal to 20 mm) s.c. MOPC-315 tumor and extensive metastases (Mokyr et al., Cancer Res., 49: 4597-4606, 1989). Here we show that as a consequence of low-dose L-PAM therapy, CD8+ T-cells accumulate in the s.c. tumor nodules of MOPC-315 tumor bearers. Specifically, an 80-fold increase in the number of CD8+ T-cells was seen within 5 days after the chemotherapy. Treatment of MOPC-315 tumor bearers with low-dose L-PAM in conjunction with monoclonal anti-Thy-1.2 or anti-Lyt-2.2 antibody, in contrast to treatment with monoclonal anti-L3T4 antibody, prevented the appearance of the massive CD8+ T-cell infiltrate in the s.c. tumor nodules. Fresh CD8+ T-cells derived from s.c. MOPC-315 tumor nodules that were regressing as a consequence of low-dose L-PAM therapy exhibited a potent direct lytic activity against the MOPC-315 plasmacytoma in a short-term in vitro assay. The specificity of the lytic activity exhibited by the CD8+ T-cells was illustrated not only by the inability of the CD8+ T-cells to lyse two antigenically unrelated thymomas (the WEHI 22.1 and the EL-4) and a natural killer-sensitive lymphoma (the YAC-1), but also by their relatively weak lytic activity against an antigenically related plasmacytoma (the MOPC-104E). Thus, CD8+ T-cells that infiltrate the s.c. tumor nodules of MOPC-315 tumor bearers following low-dose L-PAM therapy most likely exploit a CTL-type lytic mechanism to eradicate at least part of the large tumor burden not eliminated by the direct antitumor effects of the drug.
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PMID:Importance of tumor-specific cytotoxic CD8+ T-cells in eradication of a large subcutaneous MOPC-315 tumor following low-dose melphalan therapy. 212 40

The systemic administration of high dose recombinant interleukin 2 (RIL-2) can mediate significant reductions in the number of hepatic metastases in a murine system. This effect is sensitive to host irradiation. Both large granular (LGLs) and small (SLs) lymphocytes have been implicated as the cells mediating the antitumor effect. Utilizing selective Percoll fractionation of liver nonparenchymal lymphoid cells, we have attempted to determine the cell types involved in tumor immunotherapy of murine liver metastases during RIL-2 administration. At a RIL-2 dose of 25,000 units given i.p. three times a day, the total number of lymphoid cells seen in murine livers reached a peak on day 6 after the onset of RIL-2 therapy, lasting until day 10 and ranging from 25 to 29 times baseline values. Both LGLs and SLs were identified and SLs made up over one-half the cells present in murine livers. Phenotypic analysis of LGLs and SLs revealed that during exposure to RIL-2, bands 5 + 6 SLs expressed the Thy-1.2, Lyt-2, and Lyt-1 antigens to a greater degree than LGLs. LGLs exposed to RIL-2 demonstrated a decrease in the expression of the asialo GM1 antigen during exposure to RIL-2; however, the 49H.8 antigen normally expressed on natural killer cells and not on circulating T-cells was found only on LGLs. The role of murine liver LGLs and SLs needs to be further characterized.
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PMID:Analysis of liver lymphoid cell subsets pre- and post-in vivo administration of human recombinant interleukin 2 in a C57BL/6 murine system. 230 21

We examined the activities of activated lymphocytes, interferon-gamma (IFN-gamma), and interleukin 2 (IL-2) in adoptive immunotherapy of pulmonary metastases. Pulmonary metastases produced in Balb/c mice by a single tail-vein injection of 5 X 10(5) murine sarcoma (MCB8) tumor cells on day 0 were treated with combinations of Con A-activated lymphocytes (CAL) (3 X 10(7) cells on days 3 and 7), IL-2 (5 X 10(4) U three times a day on days 3 to 8), and IFN-gamma (5 X 10(4) U/mouse on days 1 to 8). Treated tumors contained increased numbers of infiltrating Thy-1.2+ lymphocytes and a predominance of L3T4+(CD4+) lymphocytes. The level of expression of class I and class II MHC antigens by tumor cells in the lung was increased after treatment. Mice that received CAL + IL-2 + IFN-gamma showed approximately 80% reduction in tumor burden as compared to controls (P = 0.001). Mice treated with IL-2 + CAL, or IL-2 + IFN-gamma, displayed approximately 50% reduction (both P less than 0.02 as compared to triple therapy), whereas IL-2, IFN-gamma, or CAL administered as single agents had little effect on pulmonary metastases. We conclude that adoptive immunotherapy with activated lymphocytes and IL-2 is enhanced by IFN-gamma.
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PMID:Adoptive immunotherapy of murine pulmonary metastases with interleukin 2 and interferon-gamma. 251 74

Immunoperoxidase localization of monoclonal antibodies in sections of melanoma has been used to identify histological features which may be of prognostic importance in melanoma, in particular whether certain structures on melanoma cells may determine the degree and nature of lymphoid infiltrates and whether these may be related to prognosis. Monoclonal antibodies to lymphocyte subpopulations were used to identify and quantitate lymphoid infiltrates in 15 primary melanomas and 8 cutaneous metastases. These were correlated with histological features identified in routine sections. There was a wide variation in the numbers of mononuclear cells associated with both primary and metastatic melanoma. T cells and to a lesser extent macrophages accounted for the majority of the cells, B cells and natural killer (NK) cells for only 2% of the infiltrates. The Leu 3a (helper) T cell subpopulation predominated in primary tumours, OKT8 positive (suppressor/cytotoxic) cells in metastases. Infiltrates in which OKT8 cells predominated were associated with ulceration, a high mitotic rate and thick primary tumours. The converse applied to Leu 3a infiltrates. Infiltrates with a high proportion of Leu 3a positive cells tended to be associated with Thy-1 positive, DR antigen negative tumours. Thy-1 antigens were predominantly expressed on primary tumours and rarely on metastases whereas the converse applied to expression of the acute lymphoblastic leukemia antigen (CALLA) on melanoma cells. These findings suggest that certain melanoma antigens may be related to the nature of the lymphoid infiltrate associated with melanoma and possibly with the behaviour of the tumour in the host. They further suggest that identification of cell surface structures and lymphoid infiltrates by these techniques may be a valuable extension of routine histopathological assessment of prognosis in melanoma.
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PMID:Current research on immunopathology of melanoma: analysis of lymphocyte populations in relation to antigen expression and histological features of melanoma. 286 82


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