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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current standard therapies for metastatic malignant melanoma are poor, and surgical excision of disease remains the cornerstone of melanoma management. Unmodified monoclonal antibodies have been used therapeutically in this, and other, malignancies, but results have been disappointing. This has led to attempts to improve the efficacy of monoclonal antibodies by using them to target therapeutic modalities to tumors. These therapeutic modalities include chemotherapeutic, radiotherapeutic and cytotoxic agents. An example of the latter is ricin A-chain, which is so potent that it has been reported that one molecule of it entering the cytosol is sufficient to cause cell death. Preclinical studies support the potential of immunotoxins as effective therapy for malignancy. A phase I-II trial of immunotoxin therapy of malignant melanoma has been completed and a trial to determine clinical efficacy has been implemented.
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PMID:Immunotoxin therapy of malignant melanoma. 354 27

Cells of B16 mouse melanoma grown in serum-free medium in the presence of [3H]glucosamine secreted or shed labeled glycoproteins. A wheat germ agglutinin-binding glycoprotein was isolated that accounted for 37% of the total [3H]glucosamine incorporated; it had a molecular weight of approximately 50,000 and was absent in less-tumorgenic wheat germ agglutinin (isolectin I)-resistant variants of the cells. The glycoprotein contained approximately 25% of serine and threonine plus equimolar amounts of glucosamine and galactosamine, indicating both N- and O-linked oligosaccharide chains. Neuraminidase treatment released approximately 60% of the glycoprotein's 3H radioactivity as N-acetylneuraminic acid. The sialoglycoprotein did not, but the desialylated species did, bind (97%) to ricin-Sepharose, suggesting the presence of terminal sialic acid and penultimate galactose residues in most of the saccharide units. Alkaline borohydride released 61% of the glycoprotein's radioactivity as oligosaccharide alcohols that were mainly tetrasaccharides (75%) with some branched trisaccharides (10%) from the O-linked structures. Hydrazinolysis and analysis of the alkaline borohydride-resistant portion of the glycoprotein indicated the presence of mainly triantennary, complex-type structures (N-linked) containing three sialic acids residues plus L-fucose. Serial lectin-affinity chromatography of the hydrazine-released saccharides with concanavalin A-agarose, pea lectin-agarose, L-PHA-agarose, and E-PHA-agarose, indicated the absence of high-mannose or hybrid-type structures and further confirmed the presence of triantennary, complex-type units.
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PMID:Isolation and characterization of a wheat germ agglutinin-binding glycoprotein from B16 mouse melanoma cells. 376 3

Cloned lines from 4 different families of B-16 melanoma cells were heated repeatedly in tissue culture at 45 degrees C with step-up time intervals. These lines included the partially heat-resistant lines previously selected at 43 degrees C(HR 43 degrees) from wheat-germ-agglutinin-resistant mutant (WGAR, HR43 degrees), concanavalin-resistant mutant (conR-HR 43 degrees), ricin-resistant mutant (ricinR, HR 43 degrees), and parental B-16 (B-16, HR 43 degrees) cells. The heating cycles were repeated 7 to 11 times at 45 degrees C increasing from 45 min to 150 min with 3 weeks of culturing at 37 degrees C between cycles. Heat resistance in most cases increased progressively with each heating step. An extensive library of mutants was thus generated, varying in the degree of heat resistance and the apparent stability. HR variants from the WGAR family appeared to be the most resistant and the most stable. The heat-resistant phenotype was expressed not only by increased survival after a normally lethal heat dose, but also by protection against heat-mediated suppression of proteins and DNA syntheses. Protein synthesis in the heat-resistant cells was not only less suppressed by heat shock, but also recovered more rapidly after removal of shock. Clinical implications of these results and the potential usefulness of the mutant lines for genetic studies are discussed.
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PMID:Heat-resistant mutants of B-16 melanoma cells. I. Stepwise heating in vitro induces progressive increase in resistance to heat. 403 Jan 40

A fetal antigen (FA) was isolated from spent culture medium of a melanoma (M14) cell line. Allogeneic serum samples from melanoma patients, previously characterized with respect to anti-FA activity, were used as the source of anti-FA antibody. The FA activity was partially purified by membrane ultrafiltration, gel filtration, and chloroform:methanol extraction. The partially purified FA was then used to develop an enzyme-linked immunosorbent assay (ELISA). By indirect ELISA both the IgG and IgM classes of anti-FA antibodies were detected in the sera of cancer patients and normal volunteers. The incidences of anti-FA antibodies in the sera of cancer patients and normal volunteers were not significantly different. As detected by competitive inhibition in ELISA, FA activity was widely distributed among melanoma, sarcoma, and carcinoma tumor tissues and cultured tumor cells, as well as among fetal brain, skin, and muscle tissues. FA activity was destroyed by treatment with beta-galactosidase and hyaluronidase, but it was not destroyed by proteolytic and lipolytic enzymes. The antigen bound to immobilized ricin, peanut, and soybean lectins. FA activity in material purified by ricin-affinity chromatography was associated with molecules in the 60,000- to 70,000-dalton region as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These results suggest a glycoprotein nature for the FA isolated from the spent culture medium of melanoma (M14) cells; this FA apparently elicits formation of natural antibodies in the cancer patients and normal donors.
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PMID:Immunochemical characterization of fetal antigen isolated from spent medium of a human melanoma cell line. 619 35

Mouse B16 melanoma cells respond to melanocyte-stimulating hormone (MSH) or cholera toxin (CT) with an accumulation of cAMP. The kinetics and dose-response of MSH were examined in the B16 parent line and two cell clones derived from it that exhibited wheat germ agglutinin (WGA) resistance [1]. These WGA lectin-resistant cells, designated W4 and W5 showed a greater response to MSH and CT than the parent B16 cells. Exposure of the W4 and W5 cells to lotus lectin or ricin respectively, led to the previously described [2] selection of cell clones that were resistant to lotus lectin (W4L) and ricin (W5R). The W4L and W5R cells which were shown [2] to be as sensitive as the B16 parent to WGA (i.e., were phenotypically reverted to WGA sensitivity), were also found to respond to MSH in a manner similar to the B16 parent. Since lectin sensitivity has been directly correlated in these cell clones with the membrane's oligosaccharides and glycopeptide pattern, these data suggest that the cellular binding and/or biological response to hormones is influenced by the carbohydrate composition of the plasma membrane.
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PMID:Lectin-resistant B16 melanoma cells exhibit an altered response to MSH and cholera toxin. 631 64

Stable heat-resistant clones were selected from wild-type B-16 melanoma cells and from three of their surface variants resistant to the lectins wheat-germ agglutinin, ricin and concanavalin A. The selection procedure included three or four cycles of heating the cells in culture at 43 degrees C for 2-1/2 to 3-1/2 h interspersed with growth at 37 degrees C. The survivability of the heat-resistant (HR) variant cells at elevated temperatures of 43 degrees C for 160 min and 45 degrees C for 40 min was 2-4 logs greater than that of their respective parents. This acquired property of heat resistance appeared to be a stable phenomenon, persisting in these cell lines for more than 80 generations. One HR variant cell line carried in tissue culture for 250 generations showed no change in the heat-resistance characteristic. Acquisition of resistance appeared to be a gradual process with intermediate stages preceding the more pronounced degree of resistance. These newly selected HR variants join the existing surface variants of B-16 melanoma to result in a large family of variants from the same cell lineage to make this system a powerful tool for studying the relationship between heat sensitivity, metastasis and hyperthermia treatment of cancer.
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PMID:Stable heat-resistant clones selected from wild-type and surface variants of B-16 melanoma. 664 53

Lectin-resistant variants of B-16 melanoma cells were selected with wheat-germ agglutinin, ricin and concanavalin A. They exhibited altered metastasizing capacity and tumorigenicity in C57BL mice. Several in vitro properties were defined and compared including homotypic adhesiveness, microfilament organization, melanin release, activity of tyrosine hydroxylase, DNA content, and karyotypes. The possible relevance of these properties in vitro for the malignant behavior displayed in vivo is discussed. The usefulness of this approach of selecting surface variants to study the problem of metastasis is also discussed.
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PMID:Lectin-resistant variants of mouse melanoma cells. II. In vitro characteristics. 668 6

The kinetics of cytotoxicity induced by ricin and a series of immunotoxins consisting of ricin A-chain coupled to antibodies against cell-surface antigens has been studied. The inhibition of protein synthesis in cells treated with immunotoxins or ricin occurs after a lag period. The rate of protein synthesis decreases according to a mono-exponential function, indicating a first-order process. With increasing concentration of immunotoxin, a maximal rate of inhibition is reached. The inactivation rate induced by immunotoxins was much slower than that achieved with ricin, even when products were compared on a basis of an identical number of molecules bound per cell, demonstrating the real higher efficacy of ricin. The time required to reduce protein synthesis by 90%, denoted T10, was 1.4-1.6 h with ricin, 60 h with anti-T65 immunotoxin on CEM human T leukemia cells (T65 positive), 65 h with anti-p97 immunotoxin on SK-MEL 28 human melanoma cells (p97 positive), and 20 h with an IgM anti-Thy 1.2 immunotoxin on WEHI-7 mouse T leukemia cells (Thy 1.2 positive). In this latter case, when the IgM antibody was replaced by an IgG anti-Thy 1.2, a 5-fold increase in the inactivation rate was obtained, demonstrating the importance of the binding moiety for the immunotoxins. Lysosomotropic amines such as ammonium chloride, chloroquine, and methylamine and carboxylic ionophores such as monensin, which are known to interfere with the uptake of certain macromolecules, strongly increased the rate of protein synthesis inhibition by all immunotoxins tested and increased 4-50,000-fold the sensitivity of cells to the immunotoxin. Enhancement in the inactivation rate was as much as 7-10-fold when either of these compounds was added, generating T10 values comparable to those of ricin.
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PMID:Kinetics of cytotoxicity induced by immunotoxins. Enhancement by lysosomotropic amines and carboxylic ionophores. 674 51

In the search for the biochemical basis of the control of glycosylation of cell surface carbohydrates, revertant clones were isolated from previously characterized wheat germ agglutinin-resistant clones of B16 mouse melanoma cells by selection for resistance to Lotus tetragonolobus lectin or to ricin. Comparison of the wheat germ agglutinin-resistant clones with the parent and revertant clones indicated that this phenotype was correlated with an increased sensitivity to the Lotus lectin, a 60- to 70-fold increase in alpha 1 leads to 3 fucosyltransferase activity and a decreased sialic acid content of the N-glycosidic chains of glycoproteins. The results suggest a novel type of control mechanism for lectin resistance, an increase in a glycosyltransferase activity. The presence of alpha 1 leads to 3 bound fucose on N-acetylglucosamine residues would interfere with the addition of sialic acid by alpha 2 leads to 3 linkages to galactose residues in the carbohydrate units, and this change could explain the resistance to wheat germ agglutinin and the increased sensitivity to the Lotus lectin. A change in a regulatory gene for the fucosyltransferase as a possible primary cause for the changed phenotype is discussed.
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PMID:Enzymatic basis for a lectin-resistant phenotype: increase in a fucosyltransferase in mouse melanoma cells. 689 97

Ricin A-chain, the toxic subunit of the potent plant toxin ricin, has been isolated by affinity chromatography and conjugated via a disulfide linkage to affinity-purified goat anti-carcinoembryonic antigen (CEA) antibody. Such conjugates retained the integrity of their antibody-combining site, as demonstrated by the ability to displace 125I-labeled anti-CEA antibody bound to CEA-positive cell lines. In addition, such conjugates retained A-chain activity, producing inhibition of [14C]leucine incorporation into a CEA-negative G-361 human melanoma cell line at concentrations similar to those of unconjugated A-chain. However, these conjugates were 40 times as potent in the inhibiton of [14C]leucine incorporation in the CEA-bearing WiDr human adenocarcinoma cell line as A-chain alone or as an unreacted mixture of A-chain and specific antibody. Such toxicity could be blocked by preincubation of the conjugate with fluid-phase CEA. Complete inhibition of [14C]leucine incorporation as well as inhibition of cellular proliferation by the conjugate was seen at 50 nM concentration. Conjugates that combine the determinant specificity of an antibody with the toxicity of ricin A-chain may show promise as selective cytotoxins for cells bearing CEA.
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PMID:Selective cytotoxicity of a ricin A-chain-anti-carcinoembryonic antigen antibody conjugate for a human colon adenocarcinoma cell line. 695 57


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