Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various subpopulations of human leukocytes may be induced by lymphokines to exert cytotoxic activity. In man major histocompatibility complex non-restricted tumor cell lysis by interleukin-2 (IL-2) induced peripheral blood lymphocytes is attributed mainly to natural killer cells. These T cell receptor negative large granular lymphocytes are called lymphokine activated killer (LAK) cells. In order to explore the potential of LAK cells in tumor therapy, several clinical studies have been conducted, using IL-2 alone or in combination with ex vivo IL-2-activated peripheral blood lymphocytes. Objective responses have reproducibly been achieved only in renal cell carcinoma and malignant melanoma and were associated with considerable toxicity. In view of restricted efficacy and increasing doubts as to whether LAK cells indeed account for the in vivo observed responses, more recent strategies focus on tumor antigen specific cytotoxic T cells or tumor infiltrating lymphocytes. Successful translation of this approach into clinical practice, however, may be dependent on some basic problems of tumor immunology to be solved which were thought to be by-passed by the LAK cell approach.
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PMID:Lymphokine activated killer cells. 267 22

Recent studies indicate that different types of antitumour lymphocytes (T and non-T) can be generated in vitro and in vivo after exposure to recombinant interleukin-2 (rIL-2). In vitro it is possible to selectively expand the CD3 cells by using anti-CD3 monoclonal antibody and rIL-2. Adherence can select a minor subpopulation of lymphokine-activated killer (LAK) cells (A-LAK) endowed with a higher lytic activity. We have investigated whether melanoma-specific T-lymphocytes can be obtained to be used for therapy or endogenously expanded in vivo by the appropriate use of limited amounts of rIL-2. Clonal analysis of lymphocytes obtained either from tumour lesions or from blood indicated the existence of melanoma-restricted T-lymphocytes, both with cytotoxic or helper function. Though a minority, these cells can be generated and expanded with low amounts of rIL-2 (3-30 Cetus U/ml) in the presence of autologous melanoma and B-cells. The use of rIL-1 and rIL-4, together with rIL-2 at certain phases of T-lymphocyte growth, can help in expanding more selectively the melanoma-specific cells. These T-cells are major histocompatibility complex-restricted in their killing but they also need to see adhesion molecules (ICAM-1) on the target cells. New clinical protocols can thus be conceived on the basis of some of these results.
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PMID:In vitro lymphocyte response to autologous melanoma: clues in designing new adoptive immunotherapy protocols. 269 77

Both phytohemagglutinin-induced cytotoxicity and recombinant-interleukin-2 (rIL-2)-induced lymphokine-activated killer (LAK) activity against noncultured melanoma cells were significantly reduced when peripheral blood mononuclear cells (PBMC) from patients with metastatic melanoma were incubated in RPMI medium 1640 and 10% autologous human serum instead of 10% fetal calf serum, while serum from either healthy donors or patients with primary melanoma did not affect the level of cytotoxicity. The serum-mediated suppression was not restricted by major histocompatibility complex and was time-dependent. Addition of 10% human serum from the patients with metastatic melanoma [HS-Pt(m)] to the culture of PBMC with rIL-2 at the same time or 1 day after incubation significantly inhibited LAK activity. However, addition of 10% HS-Pt(m) 2 or 3 days after incubation did not inhibit LAK activity. Incubation of PBMC for 2 h with a high dose (10(4) U/ml) of rIL-2 in the presence of 10% HS-Pt(m), followed by incubation in the absence of either rIL-2 or HS-Pt(m), did not affect LAK cell activity. These results suggest that HS-Pt(m) inhibits the early stage of LAK cell differentiation, rather than the binding of rIL-2 to PBMC or a later stage in the differentiation. In contrast to PBMC, monocyte-depleted peripheral blood lymphocytes exhibited comparable levels of LAK activity when cultured with rIL-2 either in 10% fetal calf serum, 10% human serum from healthy donors or 10% HS-Pt(m). Addition of purified autologous monocytes to the culture of monocyte-depleted peripheral blood lymphocytes with rIL-2 suppressed LAK cell induction when 10% HS-Pt(m) was present. Thus serum-mediated suppression of LAK cell induction is largely dependent on the presence of monocytes, which may produce a secondary inhibitor that acts on lymphocytes. Addition of indomethacin to the culture did not reverse this monocyte-dependent serum-mediated suppression in a majority of cases, suggesting that prostaglandin E2 does not have a major role in the suppression.
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PMID:Monocyte-dependent, serum-borne suppressor of induction of lymphokine-activated killer cells in lymphocytes from melanoma patients. 278

Treating human melanoma lines with dibutyryl adenosine 3':5'-cyclic monophosphate (dbc AMP) resulted in morphologic changes associated with the altered expression of cell surface antigens. After treatment, cells developed long cellular projections characteristic of mature melanocytes and showed the presence of an increased number of Stage II premelanosomes. In addition, induction of melanin synthesis, detected as brown perinuclear pigmentation, was observed. The AMP further drastically reduced the growth rate of the five melanoma cell lines that were tested. The influence of dbc AMP was completely reversible 3 days after the agent was removed from the culture medium. The antigenic phenotype of the melanoma lines was compared before and after dbc AMP treatment. This was done with four monoclonal antibodies directed against major histocompatibility complex (MHC) Class I and II antigens and 11 monoclonal antibodies defining eight different melanoma-associated antigenic systems. Treatment with dbc AMP reduced the expression of human leukocyte antigen (HLA)-ABC antigens and beta-2-microglobulin in five of five melanoma lines. In the two HLA-DR-positive cell lines dbc AMP reduced the expression of this antigen in one line and enhanced it in the other. No induction of HLA-DR or HLA-DC antigens was observed in the Class II negative cell lines. Furthermore, dbc-AMP modulated the expression of the majority of the melanoma antigenic systems tested. The expression of a 90-kilodalton (KD) antigen, which has been found to be upregulated by interferon-gamma, was markedly decreased in all the five cell lines. A similar decrease in the expression of the high molecular weight proteoglycan-associated antigen (220-240 KD) was observed. The reduced expression of Class I and II MHC antigens as well as the altered expression of the melanoma-associated antigens studied were shown to be reversible after dbc AMP was removed. Our results collectively show that the monoclonal antibody-defined melanoma-associated molecules are linked to differentiation. They could provide useful tools for monitoring the maturation of melanomas in vivo induced by chemical agents or natural components favoring differentiation.
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PMID:Cyclic AMP induces differentiation in vitro of human melanoma cells. 283 5

Previous studies from our laboratory have suggested that melanomas can be grouped in subsets reflecting stages of melanocyte differentiation. Each of these stages has a characteristic cell surface antigenic phenotype. We have examined the effect of culture of melanoma cell lines representing different stages of differentiation in RPMI medium containing insulin, transferrin, and selenium (ITS). Only cell lines with a phenotype corresponding to early or intermediate stages of melanocyte differentiation could be adapted to culture in ITS medium. ITS cultures showed a decreased reactivity with monoclonal antibodies detecting epidermal growth factor receptor and transferrin receptor. Decreased reactivity with anti-epidermal growth factor receptor antibodies was the result of the production of epidermal growth factor receptor-binding molecules by melanoma cells and down-regulation of the receptor, while decreased cell surface expression of transferrin receptors seemed related to redistribution of receptor molecules to an intracellular pool. Culture of Ia-negative melanomas in ITS medium resulted in expression of major histocompatibility complex Class II antigens. Induction of Ia antigen by culture in ITS medium was constitutive and irreversible. No coordinate changes in phenotypic traits suggestive of induction of differentiation were observed. Melanoma cell lines respond differentially to growth factors, and expression of growth factor receptors and other cell surface molecules is regulated by culture conditions.
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PMID:Surface antigens of human melanoma cells cultured in serum-free medium: induction of expression of major histocompatibility complex class II antigens. 296 39

The bicyclic anhydride of DTPA-1-14C (BADTPA-1-14C) was synthesized and reacted with an antibody to human melanoma associated antigen (MAA) and with one to human class II major histocompatibility complex antigen (HLA-DR). DTPA-1-C incorporation per mole of anti MAA at molar ratios of 1:1 to 200:1 ranged from 0.5 to 25, while immunoreactivity ranged from 49 to 9%. With antibody to HLA-DR, results were similar. Anti MAA, but not anti HLA-DR, demonstrated polymerization upon conjugation. BADTPA-1-14C provides a convenient and accurate method for measuring the amount of DTPA in monoclonal antibody preparations and its effect on immunoreactivity.
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PMID:A method for direct quantification of the amount of DTPA in 111In monoclonal antibody preparations. 304 Jun 33

Two Lyt-1+, L3T4a+ autoreactive T cell clones specific for self-class II major histocompatibility complex (MHC) gene products were established from lymph node cells and spleen cells of C57BL/6J mice, respectively, by different methods. They were stimulated to proliferate in culture in response to I-Ab antigen-bearing syngeneic spleen cells in a class II MHC-restricted manner. This stimulation was inhibited completely by the addition of anti-L3T4a (GK1.5) or anti-I-Ab (3JP) monoclonal antibodies. The autoreactive T cell clones lysed syngeneic I-Ab+ target cells such as lipopolysaccharide (LPS) blasts. They also lysed I-A- bystander cells such as Cloudman and B16 melanoma and lymphoid tumor cells in the presence of I-Ab+ stimulator cells but not I-Ad+ cells. This bystander killing was most likely mediated by soluble factors released from the autoreactive T cells in response to I-Ab antigens, because culture supernatants from activated autoreactive T cells inhibited the proliferation of B16 melanoma cells in vitro and also had significant cytolytic activity. Both lymphotoxin and interferon-gamma were released from activated autoreactive T cells, suggesting that these cytotoxic lymphokines were responsible for autoreactive T cell-mediated cytolysis. The finding that the two clones, established independently and by different methods, show self-class II MHC antigen-restricted cytolysis, and bystander cytolysis suggests that these properties are not restricted to a unique population of autoreactive T cells. These results favor the concept that in vivo, autoreactive T cells may express not only regulatory activity in regard to antibody responses, but also anti-tumor activity via bystander cytolysis.
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PMID:Anti-tumor activity of class II MHC antigen-restricted cloned autoreactive T cells. I. Destruction of B16 melanoma cells mediated by bystander cytolysis in vitro. 310 9

The relationship between major histocompatibility complex (MHC) antigens and metastasis was investigated on B16 melanoma variants. B16 cell lines express low amounts of murine MHC (H-2) antigens. A high expression can be induced in line B16-A by in vitro treatment with immune interferon (IFN-gamma) or by in vivo transplant in allogeneic mice. The increase of H-2 antigens correlated with an enhancement of lung colonization in young syngeneic mice. The higher metastatic capacity of B16-A cells with induced high levels of H-2 antigens was observed also in adult mice and in young mice pretreated with cyclophosphamide. These results were confirmed investigating the behaviour of a mutant B16 clone (B78H1) which was selectively resistant to the H-2-inducing action of IFN-gamma: lung colonization ability was not increased by IFN pretreatment. The study of variants derived from individual B16-A lung colonies revealed a wide range of H-2 levels. Variants with a low expression had a low colonization ability; one out of two variants with a high H-2 expression also was poorly colonizing. IFN-gamma-mediated H-2 expression appeared to act as an enhancer, rather than a determinant of B16 metastatic capacity.
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PMID:Interferon-mediated enhancement of metastasis. Are MHC antigens involved? 311 68

The melanoma-associated antigen P3.58 is rarely found on benign proliferating melanocytes but is consistently expressed on advanced malignant melanomas which have a high probability of metastasis. Previous studies have shown that its expression on normal tissues is limited to vascular endothelia and lymphoid follicle germinal centers and that it is also expressed by activated monocytes in vitro. In the studies reported here, anti-P3.58 monoclonal antibodies (mAb) were shown to partially inhibit antigen-specific and anti-CD3-induced T cell proliferation and to completely block a lymphocyte/monocyte clustering which occurs in the absence of added antigen. This inhibition is highly specific for P3.58 mAb and was not affected by mAb directed to major histocompatibility complex or T cell antigens. P3.58 therefore seems to be involved in an antigen-independent attraction or adhesion of lymphocytes. P3.58 is the second example (HLA-DR being the first) of an association between the expression of an immune function-associated molecule and the development of metastatic disease in melanoma.
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PMID:The tumor progression-associated human melanoma antigen P3.58 mediates monocyte-lymphocyte interactions in vitro. 322 Jan 5

Lymphocytes from human peripheral blood incubated with interleukin-2 (IL2) develop lymphokine-activated killer (LAK) activity with the ability to kill a wide variety of tumor cells in a non-major histocompatibility complex-restricted manner. Adoptive immunotherapy with LAK cells and IL2 has been reported to lead to a regression of solid tumors in some patients with advanced malignancies. Aiming to improve the effectiveness of clinical adoptive immunotherapy, we developed a procedure for selective enrichment from human blood mononuclear cells (MNC) of IL2-activated antitumor effector cells. These cells, termed adherent LAK (A-LAK) cells because of their characteristic property of adherence to plastic, demonstrated both higher proliferative potential and greater antitumor cytotoxicity than unseparated MNC. Human A-LAK cells represented only 1 to 4% of IL2-activated MNC at 24 h but expanded from 130- to 1100-fold in 20 days. They comprised a population highly enriched in CD3-Leu19+ effector cells with antitumor activity against fresh human solid tumor cells and established cell lines. A-LAK cells retained antitumor activity for up to 14 days when cultured in the presence of IL2. They also mediated antibody-dependent cytotoxicity. Large-scale generation of A-LAK cells from the blood of patients with cancer proved feasible and should yield populations that are effective in vivo at lower doses than those required with unseparated LAK cells. This offers the potential for improving the antitumor effects, reducing the toxicity, and facilitating the administration of adoptive immunotherapy in humans. A Phase I/II clinical trial utilizing A-LAK cells and IL2 in patients with melanoma and renal cell carcinoma is now in progress.
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PMID:A new approach to generating antitumor effectors for adoptive immunotherapy using human adherent lymphokine-activated killer cells. 325 68


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