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)

The processes of lymphocyte-endothelial cell interaction and the in vitro assays employed in their study are the subjects of this review. In motility assays in porous filters and gel matrices, it has been shown that lymphocyte migration can be modulated by interleukin-2 (IL-2), IL-3, IL-4, IL-6, and IL-8. Cytokines can also modulate lymphocyte-endothelial adhesion. Endothelial intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are induced or upregulated by IL-1 or tumor necrosis factor. In addition, interferon-gamma upregulates ICAM-1, and IL-4 can induce VCAM-1. The roles of these cytokines and adhesion molecules in transendothelial migration may be studied in assays in which lymphocytes penetrate layers of cultured endothelial cells. These models can distinguish lymphocyte adhesion from subsequent migration. Using such models, we and others have obtained evidence that both lymphocyte function-associated antigen-1 (LFA-1)/ICAM-1 and very late activation antigen 4 (VLA-4)/VCAM-1 interactions mediate lymphocyte adhesion to endothelial cells, but that LFA-1/ICAM-1 interactions play a greater role in transendothelial migration.
Invasion Metastasis 1992
PMID:In vitro models of lymphocyte transendothelial migration. 138 72

Tumor infiltrating lymphocytes (TIL) play an important role in the host immune response to cancer. When these cells are reinfused into cancer patients after in vitro expansion with lymphokines such as interleukin 2 (rIL-2), they often induce regression of tumor metastases. We obtained TIL of enzymatic digestion of 7 human solid tumors and then cultured them with rIL-2 and interleukin 4 (IL-4) at different concentrations for about 36 days. Immunophenotypic analysis was performed at the end of the second and fourth week; cytotoxic activity against autologous and heterologous targets was assessed on the 30th day of culture. The best lymphocytic growth was observed when we used rIL-2 and IL-4 for the first two weeks of culturing and then continued with rIL-2 alone. CD3 and CD56 cells formed the majority of TIL in all cultures. In 4 cases CD4 cells predominated at the initial stage of culturing, with CD8 cells gradually increasing and finally inverting the CD4/CD8 ratio. Autologous cytotoxicity (3/4 cases) appeared to be better in those patients in whom the CD4/CD8 ratio was inverted. These data enable identification of the combination of lymphokines that will will best provide expansion of live TIL active against tumoral cells. This procedure must be followed before in vivo reinfusion of expanded lymphocytes is carried out.
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PMID:[Analysis of growth, phenotype and cytotoxic activity of tumor infiltrating lymphocytes expanded in vitro with interleukin-2 and interleukin-4: preliminary results]. 138 39

Oligoclonality was investigated in interleukin-2 (IL-2)-activated T cells (tumor-infiltrating lymphocytes, TILs) residing in metastatic melanomas using seven different monoclonal antibodies (mAbs) specific for T-cell receptor (TCR) V alpha or V beta regions and flow cytometry. IL-2-activated TILs from 25 of 42 metastatic melanomas (60%) displayed oligoclonal expansion, whereas IL-2-activated peripheral bllod mononuclear cells (PBMCs) from only 2 of 20 patients (10%) did so during 2-5 weeks in culture. Skin-derived lymphocytes from 20 patients were cultured; only four samples proliferated and none showed oligoclonal expansion. Preferential oligoclonal expansion of TILs was observed in V beta 8+ cells (10/42, P less than 0.05), V beta 6.7+ cells (7/42, P less than 0.05), and V alpha 2+ cells (7/42, not significant). Oligoclonal expansion of V beta 8+ cells was primarily found in T cells from subcutaneous metastases (8/20 cases, P less than 0.05), whereas that of V beta 6.7+ cells and V alpha 2+ cells was also found in T cells from lymph node or organ metastases. These mAbs to TCR V regions stimulated effector TILs to produce interferon-gamma, but not IL-2 or IL-4. Subcutaneous tumor-specific (V beta 8+ cells) and non-specific (V beta 6.7+ cells and V alpha 2+ cells) oligoclonalities were observed in IL-2-activated melanoma TILs, suggesting different immune responses among different sites of metastases.
Clin Exp Metastasis 1992 Jan
PMID:Oligoclonal expansion of V beta 8+ cells in interleukin-2-activated T cells residing in subcutaneous metastatic melanoma. 153 Nov 24

Polyethylene glycolated (pegylated) interleukin-2 (PEG IL-2) was administered as a weekly i.v. bolus to patients with metastatic cancer in a phase-I trial. Efficacy, toxicity and pharmacokinetics have been described previously. To explore mechanism of IL-2 action and discover predictors of efficacy, the levels of several lymphokines were measured in pharmacokinetic serum samples. IL-1 beta and IL-6 were elevated in many patients before PEG IL-2 administration, forming a continuous, log-normal distribution among patients. The levels of the two lymphokines were strongly correlated. However, no significant correlation could be found between these levels, clinical chemistry, or tumor regression seen after PEG IL-2 administration. Three hours after PEG IL-2 administration, IL-1 beta and IL-6 levels, if elevated, fell to normal. In all patients, independent of initial levels, IL-6 and IFN-gamma, but not IL-1 beta, increased 4 to 6 h after the injection and then fell rapidly, even though PEG IL-2 levels were high and often changed only slightly during this period. This suggests an active shut down of lymphokine synthesis, or an increase in elimination rate. After the fourth administration of PEG IL-2, the peak level of IFN-gamma was 2 to 20 times higher than after the first, while the peak level of IL-6 did not change in a consistent direction. Responding patients had typical peak levels of IL-6 and IFN-gamma. Low levels of TNF and IL-4 were occasionally seen before and after PEG IL-2 administration, but no consistent pattern was evident.
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PMID:Suppression and transient induction of lymphokines in cancer patients after administration of polyethylene glycolated interleukin-2. 154 19

Owing to improved systemic control of widespread malignancy, neurological complications have become a major outcome factor and determinant of life quality in oncological patients. While solitary cerebrospinal metastases are often amenable to surgical and radiological treatment, the management of diffuse leptomeningeal neoplasia, mostly using combined radiochemotherapy, is still very difficult. Immunomodulative approaches represent a therapeutic alternative with increasing potential. We have analysed the natural immune response to leptomeningeal tumor invasion in 43 Patients by assessing cerebrospinal fluid (CSF) levels of albumin, IgG, IgM, interleukins (IL) 1, 2, 4 and 6, soluble IL-2 receptor (sIL-2R), interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), and the tumor markers, carcinoembryonic antigen (CEA) and alphafetoprotein (AFP). In most patients, either elevated IgG index, IgM index, CSF IL-6, or detection of CSF oligoclonal immunoglobulin bands indicated a host reaction against tumor cells. IL-1, IL-2, and IL-4 were never detected in CSF or serum. sIL-2R and IFN gamma were rarely detected and were not associated with specific malignancies. CSF TNF alpha was only detected in melanoma patients and may be a specific indicator of that neoplasm. No correlation was found between levels of the tumor markers, CEA and AFP, and parameters of the immune response such as IgG, IgM or IL-6. The demonstration of intrathecal immune activation in a majority of patients with leptomeningeal neoplasia may offer a new option for immunomodulative oncological therapy.
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PMID:[Intrathecal immune response in meningeosis neoplastica: IgG, IgM, oligoclonal bands and cytokines]. 159 86

We screened a panel of 8 primary and 21 metastatic melanoma cell lines for constitutive secretion of cytokines. Melanomas expressed bioactivity for TGF-beta (8/25 lines) and IFN (7/12), but not IL-2. Immunoassays detected IL-1 alpha (4/25), IL-1 beta (12/25), IL-6 (13/29), IL-8 (29/29), TGF-beta 2 (5/12) and GM-CSF (11/29), but not IL-3, IL-4, TNF-alpha, or IFN-gamma. There was no preferential association of cytokine production with cells cultured from primary versus metastatic disease, and only IL-8 was produced by all lines tested. These data demonstrate that cultured melanomas produce a variety of cytokines which are potentially capable of influencing tumor growth in vivo.
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PMID:Production of multiple cytokines by cultured human melanomas. 751 80

We have achieved efficient transduction of tumour metastases in vivo by the vascular delivery of retroviral producer cells. Experimental liver metastases in mice were created by intrasplenic injection of tumour cells into the portal venous circulation. Following the establishment of micrometastases, delivery of retroviral producer cells by the same route with a vector containing the Escherichia coli beta-galactosidase (lacZ) gene demonstrated selective in vivo gene transfer to tumour deposits. By this approach, two retroviral producer cell lines encoding cytokines (IL-4 and IL-2) directed tumoricidal inflammatory responses to established metastases. Cytokine gene targeting inhibited metastasis formation and caused significant overall reduction in tumour burden. These results suggest a novel therapeutic approach for the treatment of disseminated cancer.
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PMID:Gene therapy of metastatic cancer by in vivo retroviral gene targeting. 767 Apr 93

The adoptive transfer of immune T cells has been demonstrated to mediate regression of established tumors in animals, with encouraging results in human clinical trials. In animal studies, lymph nodes (LN) draining a progressively growing immunogenic tumor contain tumor-sensitized but functionally deficient T cells. These "preeffector" cells can be activated in vitro by sequential stimulation with anti-CD3 and interleukin (IL)-2 to differentiate into mature effector cells capable of mediating the regression of disseminated tumor. However, the preeffector cell response is weak during the growth of poorly immunogenic tumors such as the B16-BL6 melanoma. In this study, a clone of B16-BL6, A9, was transfected with the cDNA encoding for murine IL-4, in an attempt to enhance tumor immunogenicity. IL-4 secreting clones grew significantly slower than controls after intradermal (i.d.) inoculation, but all animals eventually succumbed to the progressive tumor. The ability of IL-4-secreting tumor cells to stimulate a preeffector cell response was then investigated. LN draining the IL-4-secreting tumors for 10 days were activated by the anti-CD3/IL-2 method. The resulting lymphocytes were adoptively transferred into animals bearing 3-day established parental pulmonary metastases. The transfer of cells derived from sensitization with the IL-4-secreting tumors was capable of significantly reducing the numbers of pulmonary metastases more effectively than cells sensitized to the parental tumor. Thus, genetic modification of tumor cells to secrete IL-4 can stimulate an increase in the preeffector cell response in the tumor-draining LN, suggesting an enhancement in T-cell-mediated immune function against the parental tumor.
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PMID:Enhancement of immune reactivity in the lymph nodes draining a murine melanoma engineered to elaborate interleukin-4. 780 30

Expression of an extended panel of cytokine genes was investigated by reverse polymerase chain reaction (PCR) in 10 freshly excised melanoma metastases infiltrated by lymphocytes (TIL). cDNA encoding for CD3-delta and tyrosinase could be amplified in all samples, confirming the presence of T lymphocytes and melanoma cells. Cytokine genes possibly transcribed by both cell types, such as GM-CSF, IL-6 and IL-10 could be amplified from 5, 2 and 2 samples respectively. In contrast, IL-1 beta and TNF-alpha mRNA were never detectable, IL-1 alpha, IL-3 and IL-7 mRNA could be observed only in one case each. Transcripts encoding for TGF-beta 1 were observed in 8 samples, while TGF-beta 2 and 3 mRNA were detectable in only 2 specimens. mRNA encoding for cytokine genes typically transcribed by antigen-stimulated T lymphocytes, such as IL-2, IL-4 and IFN-gamma were rarely or never detectable (none, none and 1 of the samples respectively). In one case, where no cytokine gene transcription was detectable at the time of surgery, we addressed the question of the antigenicity of the tumor and of the functional competence of TIL. A primary tumor cell line was generated and cultured TIL were induced to transcribe IL-2 and IFN-gamma genes by incubation with the autologous irradiated tumor cell line, but not with autologous EBV-transformed cells. In these conditions, tumor-specific cytotoxic T lymphocytes (CTL) could be generated only after 3 weekly re-stimulations. In contrast, if autologous irradiated EBV-transformed cells were added to the cultures, specific CTL could be detected after one single tumor stimulation. Thus, signs of active responsiveness in terms of lymphokine gene mRNA are seldom detectable in melanoma metastases. Tumor-specific responses, however, including IL-2 and IFN-gamma gene expression and generation of CTL can be produced in vitro from specimens in which no cytokine gene mRNA is detectable ex vivo.
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PMID:The pattern of cytokine gene expression in freshly excised human metastatic melanoma suggests a state of reversible anergy of tumor-infiltrating lymphocytes. 818 65

Optimal conditions for expanding tumor-infiltrating lymphocytes (TILs) specifically cytotoxic for autologous melanoma for clinical use have not yet been identified. In several small studies, interleukin (IL)-4 was reported to promote the growth of such TILs in IL-2. Given the potential implications for TIL therapy, we attempted to confirm these findings in a larger study. Baseline data were first obtained on the proliferation, immunophenotype, and cytotoxic reactivity to autologous melanoma of TILs cultured in IL-2 alone. Similar studies were performed with TIL cultured concurrently in either IL-2 alone or in a combination of IL-2 and IL-4. TILs were obtained by excisional biopsy of tumors from 52 patients with metastatic malignant melanoma; TILs from 38 patients were expanded in IL-2 (1,000 U/ml). TILs from 19 biopsies were maximally expanded 6- to 24,000-fold (median, 300-fold) over 4-10 weeks. Expansion did not correlate with the weight of, or number of lymphocytes in, the biopsy specimen, or the site of the biopsy (lymph node vs. subcutaneous metastases). During weeks 5-8, TILs from 19 of 25 biopsy specimens lysed autologous melanoma with little or no lysis of allogeneic melanoma. Lysis of autologous tumor was blocked by antibody to class I antigens. Twenty-four TIL specimens were cultured concurrently in IL-2 alone and in IL-2 plus IL-4 and tested for growth and for lysis of autologous and allogeneic melanomas.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth and autologous tumor lysis by tumor-infiltrating lymphocytes from metastatic melanoma expanded in interleukin-2 or interleukin-2 plus interleukin-4. 828 Jul 15


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