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 animal studies, lymph nodes (LN) draining progressive tumors contain immunologically sensitized but functionally deficient T cells. These preeffector cells can differentiate into mature effector cells on stimulation in vitro with anti-CD3 and IL-2. However, anti-CD3 react with all T cells and the activated cell population expressed a broad but normal distribution of V beta phenotypes. In this study, we examined the feasibility of using bacterial superantigens to stimulate tumor-draining LN cells. Because of their TCR V beta restriction, superantigen activation may afford a means to identify T cell subsets that are important in the antitumor immune response. Stimulation of draining LN cells with staphylococcal enterotoxins A (SEA) or B (SEB) followed by culture in IL-2 resulted in selective activation and expansion of V beta 3 and V beta 11 or V beta 3 and V beta 8 T cells, respectively. However, in adoptive immunotherapy, SEB- but not SEA-activated cells mediated the regression of established pulmonary metastases. To define the relative antitumor effects of V beta 3 and V beta 8 T cells, SEB-activated cells were depleted of either V beta 3 or V beta 8 T cells with mAb and magnetic beads. The antitumor effects were demonstratably diminished after V beta 8 cell depletion but enhanced after V beta 3 cell depletion. Using antigenically distinct MCA 205 and 207 sarcomas, tumor regression mediated by the activated cells was found to be immunologically specific for the tumor that stimulated the draining LN. Furthermore, the SEB-activated cells were virtually all T cells consisting of approximately equal proportions of CD4+ and CD8+ cells and the collaboration of the two T cell subsets was required for in vivo antitumor effects. However, the helper function of CD4+ cells could be facilitated by the administration of exogenous IL-2. Despite their in vivo antitumor reactivity, SEB-activated cells did not exhibit tumor cytotoxicity in the 4-h 51Cr release assay. However, they secreted IFN-gamma on specific stimulation with tumor cells. Taken together, these results provide for the first time clear evidence of the functional significance of superantigen interactions with immunologically committed T cells and suggest a preferential V beta use that might be associated with the T cell immune response to progressively growing tumors.
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PMID:Stimulation of tumor-draining lymph node cells with superantigenic staphylococcal toxins leads to the generation of tumor-specific effector T cells. 830 Nov 31

Cells from lymph nodes (LN) draining progressively growing tumors can differentiate into immune effector cells upon in vitro stimulation with anti-CD3 monoclonal antibodies followed by interleukin-2. The adoptive transfer of these activated LN cells to tumor-bearing mice mediates potent tumor-specific therapeutic effects. In this study, we sought to further characterize the antitumor efficacy and specificity mediated by the anti-CD3/IL-2 activated tumor-draining LN cells against heterologous clones derived from the murine MCA 106 sarcoma. Ten clones of divergent characteristics with regard to morphology, in vivo growth rate, ability to establish pulmonary metastases, MHC class I (H-2) antigen expression, susceptibility to lysis by allogeneic cytotoxic T-lymphocytes, as well as sensitivity to doxorubicin were selected and analyzed. In adoptive immunotherapy experiments, pulmonary metastases derived from each clone were found to be sensitive to the therapeutic effects of activated cells derived from LN draining the parental MCA 106 tumor. The antigenic cross-reactivity was evident from the observation that activated cells from LN draining each of the individual tumor clones were capable of mediating the regression of parental tumor metastases. The specificity of the antitumor reactivities mediated by LN cells draining MCA 106 clones was demonstrated by a lack of in vivo efficacy against metastases derived from the antigenically distinct MCA 205 sarcoma. Additionally, selected clones were tested for their ability to stimulate draining LN against other cloned tumors or used as targets for therapy with activated LN cells draining different clones. In all 29 adoptive immunotherapy experiments, there was complete cross-reactivity between different MCA 106 tumor clones. These findings suggest that the MCA 106 tumor-specific antigen(s) that stimulates draining LN in vivo and recognized by the anti-CD3/IL-2 activated cells is present on most if not all tumor cells. However, in the absence of a demonstrably resistant tumor clone, a very highly polymorphic antigen with many cross-reactive, but distinct epitopes might be operative and attributable to these observations.
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PMID:Cross-reactivity of anti-CD3/IL-2 activated effector cells derived from lymph nodes draining heterologous clones of a murine tumor. 836 26

With the aim of investigating the clinical usefulness of CEA, CA 15-3, and MCA serum levels, we studied 143 women whose breast cancer was submitted to serial tumor marker determinations: 79 women had stage I-II tumors and were undergoing follow-up after local and adjuvant treatment; 64 women presented metastatic lesions. Among the stage I-II patients, 63 women remained disease-free during the observation period and 16 developed metastases. In 13 out of 16 patients, tumor markers were elevated and in 11 out of 16 patients the increased tumor markers were the first sign of disease progression. Among metastatic patients, 49 presented increased tumor markers and 15 normal value. Moreover, we observed a decrease or normalization of tumor markers in patients responding to treatment and increased values in progressive disease. No correlation was noted between site of disease and tumor markers. We concluded that tumor markers are of clinical value in the detection of metastasis and may be useful in monitoring response to treatment in metastatic patients.
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PMID:Serum CEA, CA 15-3, and MCA in breast cancer patients: a clinical evaluation. 840 28

Gene modification of tumor cells with the cDNA for interferon gamma (IFN gamma) has been shown to increase the immunogenicity of some tumor cells. In order to explore further the possible therapeutic relevance of these previous findings, two clones of the nonimmunogenic MCA-102 fibrosarcoma of C57BL/6 origin were retrovirally transduced with the cDNA encoding murine IFN gamma: 102.4JK (4JK), a clone with relatively high major histocompatibility complex (MHC) class I expression, and 102.24JK (24JK), a clone with low expression of surface MHC class I molecules. Retroviral transduction of tumor cells with the cDNA encoding for IFN gamma resulted in a substantial up-regulation of MHC class I surface expression in the 24JK clone but little change of class I in the 4JK clone. In an attempt to generate antitumor lymphocytes, these gene-modified cells were inoculated into mouse footpads and draining lymph nodes (DLN) were removed, dispersed, and cultured in vitro for 10 days with irradiated tumor cells and interleukin-2. DLN from mice bearing either unmodified tumor or tumor transduced with cDNA encoding neomycin resistance (NeoR) or IFN gamma, were used to treat recipients harboring 3-day pulmonary metastases induced by the parental, unmodified tumor. Treatment with DLN cells obtained following the injection of 24JK tumor cells modified with the gene for IFN gamma significantly reduced the number of pulmonary metastases in four separate experiments, compared to groups treated by DLN cells generated from inoculation of either the unmodified, parental 24JK clone or the same clone transduced with the NeoR gene only. In contrast, DLN cells induced either by IFN gamma-transduced 4JK (high expression of MHC class I) or an unmodified 4JK tumor (moderate expression of MHC class I) had significant but equal therapeutic efficacy. Although the in vitro growth rate of tumor cell lines was unaffected by the insertion of the mouse IFN gamma cDNA, their in vivo (s.c.) growth rates were significantly slower than those of the nontransduced tumors. Thus, after retroviral transduction of the murine IFN gamma cDNA into a nonimmunogenic tumor with a very low level of surface expression of MHC class I, modified tumor cells could elicit therapeutic T cells from DLN capable of successfully treating established pulmonary metastases upon adoptive transfer. This strategy significantly confirms previous observations on the potential therapeutic effects of gene modification of tumor cells with IFN gamma and extends the realm of therapeutic possibilities to include the use of DLN cells for the development of T-cell based immunotherapies against nonimmunogenic human tumors.
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PMID:Retroviral transduction of interferon-gamma cDNA into a nonimmunogenic murine fibrosarcoma: generation of T cells in draining lymph nodes capable of treating established parental metastatic tumor. 840 32

Recent studies have demonstrated that noncytolytic T-cells can mediate regression of murine tumors. In this report, we demonstrate that MCA-105 tumor-draining lymph node cells (DLN) activated with the protein kinase C activator, bryostatin 1, plus a calcium ionophore are capable of inducing specific tumor regression in vivo when adoptively transferred to mice with established metastases. However, these activated DLN cells lack in vitro cytotoxicity against autologous tumor. Antibody against gamma-interferon (IFN-gamma) markedly inhibited the therapeutic efficacy of these activated DLN cells. Anti-tumor necrosis factor produced a statistically significant but weaker inhibition of tumor regression. IFN-gamma, but not tumor necrosis factor alpha, could be shown to be secreted by activated DLN cells in vitro in response to specific tumor. Secretion of IFN-gamma was primarily a function of CD8+ T-cells. IFN-gamma was not directly cytotoxic to sarcoma cells in vitro. Moreover, tumor cells incubated with IFN-gamma were not more susceptible to lysis by activated DLN cells. However, recombinant murine IFN-gamma had a significant antiproliferative effect against MCA-105 tumor cells when tested in a [3H]thymidine uptake assay. Similarly, supernatants obtained from DLN/autologous tumor cocultures markedly inhibited MCA-105 proliferation; this antiproliferative effect was abrogated by the addition of anti-IFN-gamma antibody to the cultures. These results suggest that secretion of IFN-gamma by adoptively transferred DLN cells plays an essential role in tumor rejection. The dominant effect of IFN-gamma may be its demonstrated antiproliferative activity.
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PMID:gamma-Interferon plays a key role in T-cell-induced tumor regression. 842 64

In this study, cytokine release by tumor-draining lymph node cells sensitized in vitro (IVS-TDLN) was examined and correlated with therapeutic efficacy in adoptive immunotherapy. Mice bearing immunologically distinct MCA 207 and MCA 205 sarcoma tumors were utilized in criss-cross experiments. IVS-TDLN obtained from mice bearing 10-day subcutaneous (s.c.) tumors mediated immunologically specific regression of established 3-day pulmonary metastases, but demonstrated non-specific cytolytic reactivity against both tumors in a 4-h 51Cr-release assay. By contrast, these IVS-TDLN cells were found specifically to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) when restimulated in vitro with irradiated tumor cells. To determine the predictive value of tumor-specific cytokine release with in vivo therapeutic efficacy, a kinetic analysis of antitumor activities of TDLN obtained from animals bearing MCA 207 tumors for increasing lengths of time was performed. IVS-TDLN cells from mice bearing day-7, -10 and -14 s.c. tumors manifested tumor-specific release of GM-CSF and IFN gamma, and mediated significant antitumor reactivity in vivo. In contrast IVS-LN cells from day-0 and day-21 tumor-bearing animals did not release significant amounts of GM-CSF and IFN gamma, and were not therapeutically efficacious in vivo. Day-4 IVS-TDLN released high levels of GM-CSF and IFN gamma non-specifically, and were not therapeutic in adoptive immunotherapy at doses effective for day-7 and day-14 IVS-TDLN cells. In other experiments, IVS cells generated from different lymph node groups in animals bearing 10-day established s.c. tumors were examined and found to have unique profiles of cytokine release. In these studies, the ability of IVS cells to release specifically both cytokines as opposed to one was associated with greater therapeutic efficacy on a per cell basis. Our findings suggest that the tumor-specific releases of GM-CSF and IFN gamma are useful parameters to assess the in vivo therapeutic efficacy of immune lymphocytes.
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PMID:Tumor-specific granulocyte/macrophage colony-stimulating factor and interferon gamma secretion is associated with in vivo therapeutic efficacy of activated tumor-draining lymph node cells. 853 78

The present study was carried out on 152 patients divided into three groups: A) 73 underwent radical surgery for breast carcinoma without signs of metastases; B) 31 patients with radiologic and scintigraphic evidence of bone metastases originating from malignant mammary neoplasia (14 with only one and 17 with two or more localizations); C) 48 affected by simple mammary cysts. No patients had a previous history of primary or secondary bone pathologies or renal, hepatic or endocrine ones. Besides this, no patient took drugs influencing the metabolic turnover of the bony tissue in the three months preceding the study. After surgery all patients underwent standard clinical and laboratory follow-up, the latter including, every 3 months, the evaluation of serum CA 15.3, CA 27.29 MCA, and ostase. The ostase cut-off, obtained by the statistical elaboration of the serum values of the 48 patients with benign mammary cysts and the 73 disease free patients, was 17 microg./L. The mean concentration in the three groups and two subgroups was: 13.76 microg./L (patients without metastases), 31.84 (patients with metastases), 18.4 (limited bony metastases), 40.04 (diffused bony metastases) and 5.36 (mammary cists). The diagnostic sensitivity of ostase proved superior to that of CA 15.3 (84% vs 75%) except when considering the subgroup with limited metastases (71.4% vs 72.7%), while the specificity was similar (around 78%). CA 27.29 and MCA were not useful as markers of metastasis. In a longitudinal-perspective study it was possible periodically to test these markers in 13 patients, at first, disease free and then with signs of bone progression evidence by skeletal scintigraphy. In 11 of these patients ostase and CA 15.3 showed increased values, an average 136 and 131 days respectively, before instrumental evidence of progression. None of the 13 patients, at the time of bone progression diagnosis, showed clinical, laboratory or instrumental signs of disease in other organs. The precocity of the serum increase of ostase could have a triple role: 1) accomplishment of a closer follow-up in patients at "high risk" of bone disease; 2) aid in the interpretation "in a neoplastic sense" of an "uncertain image of hypercaptation"; 3) accomplishment of a supporting or specific oncology treatment at an earlier stage which may be of some advantage as regards quality of life.
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PMID:Serum ostase in the follow-up of breast cancer patients. 857 28

The present study describes a new low molecular weight factor released by muscle cells, which inhibits proliferation of tumor cells in vitro and in vivo, is highly specific towards tumor cells, and has no observable effect on normal cells' proliferation. What first prompted us to investigate this factor was the observation that tumor metastases are extremely rare in striated muscles. Co-culturing of striated muscle cells with malignant cells led to marked morphological alterations in the latter, in contrast to the same cells when incubated without muscle cells. A conditioned medium of striated muscle cells was prepared and its effect tested on a variety of cells. This conditioned medium (CM) inhibited proliferation of tumor cell lines of murine (B16 melanoma, Madison 109 lung carcinoma, MCA-105 sarcoma, ESB lymphoma), or of human origin (HTB-38 adenocarcinoma, T47D breast carcinoma, CX1 colon carcinoma). The proliferation of normal cells (bone marrow cells, fetal liver erythroid cells) was not affected by the CM. Flow cytometric analysis of B16 melanoma cells following incubation with the CM revealed that 63% +/- 12 of the cells were in the G0/G1 phase of the cell cycle, compared to 47.8% +/- 8 of cells incubated with a medium (not conditioned) only. The activity of the CM and of certain fractions thereof was also demonstrated in vivo: they prevented tumor growth in mice inoculated intraperitoneally with MCA-105 sarcoma cells. Partial purification of the CM revealed that the active component was a non-proteinaceous compound with a molecular weight of about 500 D. The results clearly suggest that muscle cells produce a low molecular weight factor which can selectively inhibit the proliferation of tumor cells in vitro and in vivo. This factor is neither species nor tumor specific.
Clin Exp Metastasis 1996 May
PMID:Muscle cells produce a low molecular weight factor with anti-cancer activity. 867 72

Because the requirement for long-term cell culture can make adoptive cellular immunotherapy cumbersome, experiments were designed to determine whether smaller numbers of tumor-sensitized T cells activated briefly with bryostatin 1 and ionomycin (B/I) could be returned immediately to recipient mice without in vitro expansion and still have an anti-tumor effect in vivo. Popliteal tumor-draining lymph nodes (DLNs) from mice bearing progressive MCA-105 and MCA-203 footpad sarcomas were harvested and treated for 18 h with B/I. These cells were then washed and transferred immediately to naive C57B1/6 mice. In some experiments, these mice were irradiated (500 rads) before adoptive transfer and were given interleukin-2 (IL-2, 7,500 IU i.p., b.i.d. for 3 days) after receiving the activated lymphocytes. Recipient mice were challenged with sarcoma cells (4 x 10(5) i.v.) 6 to 32 days after receiving the activated lymphocytes. Mice receiving 10(6) B/I-activated lymphocytes before tumor challenge had significantly fewer metastases than did controls. This protective effect did not require exogenous IL-2 or host irradiation. Using Thy-1 congenic donors, it was shown that B/I-activated T cells expanded in recipients when IL-2 was also given, and these cells were a prominent component (15% of total cells) in the infiltrates found in the lungs of mice 7 days after i.v. tumor challenge. Combining these B/I-"pulsed" cells with cyclophosphamide (CYP) and IL-2 to treat mice with established (3-day) metastases resulted in significant reduction in pulmonary nodules, with complete regression in many of the treated mice, which was rarely seen with CYP alone or with CYP + IL-2. Thus, adoptive transfer of tumor-sensitized, B/I-activated DLN cells confers protection against i.v. tumor challenge, without prior in vitro expansion of the effector cells. Phenotyping studies demonstrate that donor cells activated with B/I do expand in recipient mice after adoptive transfer and can move to sites of tumor. Moreover, these cells can mediate a therapeutic effect on established tumor metastases, when combined with chemotherapy.
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PMID:Adoptive transfer of bryostatin-activated tumor-sensitized lymphocytes prevents or destroys tumor metastases without expansion in vitro. 877 Jul 70

Recombinant adenoviral mediated delivery of suicide and cytokine genes has been investigated as a treatment for hepatic metastases of colon carcinoma in mice. Liver tumors were established by intrahepatic implantation of a poorly immunogenic colon carcinoma cell line (MCA-26), which is syngeneic in BALB/c mice. Intratumoral transfer of the herpes simplex virus type 1 thymidine kinase (HSV-tk) and the murine interleukin (mIL)-2 genes resulted in substantial hepatic tumor regression, induced an effective systemic antitumoral immunity in the host and prolonged the median survival time of the treated animals from 22 to 35 days. The antitumoral immunity declined gradually, which led to tumor recurrence over time. A recombinant adenovirus expressing the mIL-12 gene was constructed and tested in the MCA-26 tumor model. Intratumoral administration of this cytokine vector alone increased significantly survival time of the animals with 25% of the treated animals still living over 70 days. These data indicate that local expression of IL-12 may also be an attractive treatment strategy for metastatic colon carcinoma.
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PMID:Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma. 887 30


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