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)

Radioimmunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis was used to study the distribution on human lymphoid cells of a previously undescribed surface antigen recognized by several heteroantisera. A glycoprotein with a 90,000 mol wt (under reducing conditions) was detected on all cell lines tested including T, B, null, and myeloid cell lines, although the amount of antigen present varied considerably. The antigen was absent from normal peripheral blood lymphocytes (PBL), B and T cells, monocytes, granulocytes, thymocytes, and erythrocytes. After stimulation with lectins or allogeneic B cells, the antigen was induced on PBL T cells. A limited number of leukemic T cells tested all expressed the antigen, as did melanoma cell line and human embryonic lung fibroblasts. Hence, the antigen was present only on dividing lymphoid cells and absent from nondividing cells, but was also present on the two examples of dividing non-lymphoid cells tested. Under nonreducing conditions, the 90,000-mol wt band normally present disappeared to be replaced by another at approximately 200,000 mol wt. The glycoprotein bound to lectins from lentil and ricin, but not to wheat germ agglutinin. It could be readily labeled metabolically by [35S]methionine or by surface iodination, and appeared to be a major membrane protein on some cell lines.
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PMID:Novel surface antigen expressed on dividing cells but absent from nondividing cells. 696 14

From C57BL mouse melanoma B-16 cells, variant clones were selected in vitro which were resistant to the lectins wheat-germ agglutinin and ricin. Cells were also selected which survived toxic concentrations of concanavalin A. Four different in vivo assays using intradermal, intravenous, intraperitoneal and intramuscular injections were used to assess the tumorigenicity and metastasizing capacity of these lectin-resistant variants. It was concluded that to obtain a complete picture of the malignant properties of a given cell line or clone, all four assays have to be carried out. In comparison with the parental cells, the WGA-resistant cells showed a most dramatic decrease in metastasizing capacity through both lymphatic and vascular channels. Tumorigenicity was also reduced. The ricin-resistant cells showed a defective development into lung tumors and thus displayed a reduction in metastasis through the hematogenous route. Since this line did not change its capacity to metastasize via the lymphatic route, and the tumorigenicity was not significantly altered, it will be a good model for studies seeking to dissociate these two properties. The Con-A-selected cells, when injected intravenously, developed tumor nodules in the liver in addition to those in the lungs, while no striking alterations in tumorigenicity or metastasizing capacity could be detected in this line.
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PMID:Lectin-resistant variants of mouse melanoma cells. I. Altered metastasizing capacity and tumorigenicity. 708 30

To study the usefulness of an in vitro colony-forming assay in predicting individual clinical responses to chemotherapy, tumor cells obtained from 150 melanoma metastases (119 patients) were grown in soft agar according to the method of Courtenay and Mills (1978), and tested for sensitivity to DTIC, CCNU, vinblastine, procarbazine, abrin and ricin. In 83% of the cases colony formation was observed (plating efficiency, PE, greater than 0.01%). Twenty-seven per cent of the tumors gave PEs greater than 1%, 45% gave PEs in the range 0.1-0.9%, whereas 11% of the tumors gave 0.01-0.09%. The PEs were not correlated with the degree of pigmentation or with the clinical course. Evaluable chemosensitivity data were obtained on 104 metastases from 83 patients. Large differences in sensitivity were seen. In cases which were evaluable both in vivo and in vitro a clear correlation was found between the in vitro chemosensitivity, expressed as the expected growth delay, and the clinical response to chemotherapy. Tumors from patients with partial response, mixed response or stable disease after prior progression, all had rather high in vitro sensitivity to the drug used (expected growth delay greater than 2.0), whereas patients with progression had lower sensitivity. The results confirm that the soft agar method used here provides good culture conditions for human melanoma cells and show that chemosensitivity data can be obtained in a high percentage of melanoma patients. The approach used seems promising in aiding clinicians to adjust chemotherapy to individual patients.
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PMID:Colony growth and chemosensitivity in vitro of human melanoma biopsies. Relationship to clinical parameters. 709 99

Conjugates (immunotoxins) comprising ricin A-chain and monoclonal antibody 96.5, which is specific for human melanoma-associated antigen p97, inhibited protein synthesis and colony formation of cultured human melanoma cells that expressed more than 80,000 molecules of p97 per cell. Cells expressing fewer than 5,000 molecules of p97 were not killed. The presence of 10 mM ammonium chloride significantly increased the efficiency of the immunotoxin, tumor cells expressing high levels of p97 being killed at immunotoxin concentrations as low as 10(-10) M.
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PMID:Human melanoma cells can be killed in vitro by an immunotoxin specific for melanoma-associated antigen p97. 714 40

Heterotypic adhesiveness of surface variant clones of B-16 melanoma cells exhibiting different metastasizing capacity was studied with respect to components of the vascular wall in culture including endothelial (E) and smooth muscle (SM) cells from adult bovine aorta, and the extracellular matrices laid down by them. The ricin-resistant cells (ricinR) and the wheat-germ agglutinin-resistant (WGAR) cells, both of which showed reduced hematogenous metastases in vivo, showed reduced adhesiveness specifically to endothelial cells and extracellular matrices. This reduced heterotypic adhesiveness is in contrast to the homotypic adhesive properties in which respect the ricinR cells had similar values to the parental cells, while the WGAR cells had much higher values than the latter. There appeared to be a positive correlation between metastasizing capacity and specific adhesiveness to E cells and the extracellular matrix surfaces.
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PMID:Altered adhesiveness of tumor cell surface variants with reduced metastasizing capacity--reduced adhesiveness to vascular wall components in culture. 716 Sep 43

The chemosensitivity of human melanoma cells has been studied before and after continuous in vitro culture. Altogether, nine cell lines were studied, two derived from patients' biopsies, and seven from xenografts in athymic mice. The sensitivity to the agents DTIC (Dacarbazine), CCNU (Lomustine), procarbazine, vinblastine, abrin and ricin was assayed. Furthermore, in five cases the chemosensitivity of the cell lines was compared to that of tumors obtained by injecting the cell lines into athymic mice. In all cases the sensitivity was measured in an in vitro soft agar assay. Upon cultivation in vitro, two of the cell lines, one derived from a patient's metastasis and one from a xenograft in athymic mice, showed marked increases in sensitivity to some of the drugs, whereas sensitivity to other drugs showed little or no change. For the other cell lines small, but definite increases or decreases in chemosensitivity were observed. Permanent cultures showed the same chemosensitivity as early subcultures. The tumors formed by injecting the cell lines into athymic mice showed moderate changes in chemosensitivity, as compared to the cell lines in vitro. The data indicate that considerable changes in chemosensitivity may occur when cells are brought from in vitro to in vitro conditions and vice versa and that such changes may be highly specific. Therefore, although cell lines may be useful in some respects, they should be used with caution in attempts to evaluate quantitatively the sensitivity of human tumors to cancerostatic drugs.
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PMID:The usefulness of human tumor cell lines in the study of chemosensitivity. A study of malignant melanomas. 730 86

Melanoma-associated antigens (MAA) shed into spent culture medium of intrinsically radiolabeled melanoma cells react specifically with monoclonal and polyclonal anti-melanoma xenoantiserums and are represented by two glycoproteins with molecular weights of 240,000 (240K) and 94,000 (94K): 240K is present only on melanoma cells whereas 94k is also found on carcinoma cells and on fetal melanocytes. Both 240K and 94K have been obtained radiochemically pure by utilizing cellulose ion-exchange and antibody affinity chromatography. The two antigens have different charge properties, as 240K binds to CM-cellulose while 94K does not. A difference in carbohydrate moieties is also indicated since 240K binds selectively to lentil lectin and 94K to ricin lectin. Two-dimensional gel electrophoresis an tryptic peptide maps of the two antigens reveal distinct and characteristics profiles. Subunit structure determination of both antigens suggests 94K to be a single chain whereas 240K appears to be a subunit of a larger molecular structure.
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PMID:Molecular profiles of human melanoma-associated antigens. 746 Nov 45

Antibody ZME-018 is directed against the gp240 glycoprotein on the surface of more than 80% of human melanoma cell lines and fresh biopsy specimens. Previous studies in our laboratory described the in vitro cytotoxicity and specificity of an immunoconjugate composed of mAb ZME-018 and the plant toxin gelonin. The present study described the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xenograft/nude mouse models. Pharmacokinetic studies of 125I-labeled ZME-018 and ZME-gelonin demonstrated a shorter terminal-phase plasma half-life of the immunoconjugate than native ZME (20.6 h compared to 41.3 h). The initial volume of distribution of the ZME-gelonin was also higher compared to that of ZME alone (2.85 ml compared to 1.94 ml) suggesting an enhanced distribution of the conjugate outside the vasculature. The corresponding area under the concentration/time curve for the ZME-gelonin conjugate was 40% lower than that of ZME alone (80.8 compared to 139.6 microCi.ml-1 x min). In nude mice bearing well-developed human tumor A375 melanoma xenografts, administration of 125I-labeled ZME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9 +/- 0.5 and 1.5 +/- 0.6 respectively by 72 h. Compared with ZME, ZME-gelonin conjugate caused an increase in the content of radiolabel in kidney, spleen and liver. Treatment of nude mice bearing well-developed (150 mm3) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelonin, or saline resulted in suppression of tumor growth in the immunotoxin group but virtually no retardation of tumor growth in the control groups. Using a murine model for a rapidly growing lethal metastatic human melanoma, treatment with ZME-gelonin resulted in a mean survival of 44 days, 213% increase in mean survival time compared with the saline treatment (14.2 +/- 2 day survival). Given these encouraging results, we are proceeding with further preclinical development of this immunotoxin.
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PMID:Pharmacokinetics, tissue distribution, and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin. 760 May 67

XOMAZYME-Mel (XMMME-001-RTA) is an immunoconjugate comprised of ricin A chain conjugated to a murine monoclonal antibody directed against high molecular weight melanoma antigens. Although not necessarily related to increased toxicity or decreased efficacy, the development of anti-immunoconjugate antibodies may limit repetitive dosing with an immunoconjugate. We evaluated the role of cyclosporine A in blocking the antibody response in patients with melanoma treated with XMMME-001-RTA. Patients received cyclosporine in divided daily doses to achieve serum levels by HPLC of 150-200 ng/ml on days 1-22. On day 3, XMMME-001-RTA was begun at dosages 0.2-0.6 mg/kg daily for 5 days. Treatment was repeated every 35 days. Three patients were treated in each dosage tier (0.2, 0.4, 0.6 mg/kg). Nine patients were entered and all nine were evaluable. Patients had histologically confirmed melanoma. Metastatic sites included skin, soft tissue, and lymph nodes (seven), lung (two), liver (one), and spleen (one). There were four men and five women aged 46-75 years. Toxicities included myalgia, arthralgia, hypoalbuminemia, fatigue, elevations in liver function tests, and increased peripheral edema. Four patients received two to five repeated dosages of XMMME-001-RTA. One wheal-and-flare reaction from an immunotoxin test dose of XMMME-001-RTA was noted after five cycles. After a test dose subsequent to one cycle, two patients experienced chest tightness without ECG changes and were removed from the study. All toxicities resolved without sequelae. One patient experienced partial lymph node remission for 9 months. A second patient had stable mediastinal disease for 20 months. XMMME-001-RTA is safe when given repeatedly with cyclosporine.
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PMID:Phase I/II study of murine monoclonal antibody-ricin A chain (XOMAZYME-Mel) immunoconjugate plus cyclosporine A in patients with metastatic melanoma. 847 94

The development of cellular resistance to immunotoxins has been demonstrated in a variety of models and can involve a number of mechanisms. For the present study, an immunotoxin was utilized composed of an anti-melanoma antibody ZME-018 recognizing a 240-kDa surface glycoprotein (gp 240) and the plant toxin gelonin. Human melanoma cells (A375-M) were grown in the presence of increasing amounts of ZME-gelonin and a clonal variant (A-375-ZR) was developed that was 100-fold resistant to ZME-gelonin compared to parental cells. Scatchard analysis showed that the A375-M parental cells had 260 X 10(3) ZME-gelonin-binding sites/cell with relatively low affinity (5 nM). In contrast, resistant A375-ZR cells demonstrated a reduced number of low-affinity sites (160 x 10(3)/cel1), but showed a small number (47 x 10(3)) of higher-affinity sites (0.8 nM). Internalization rates and degradation rates of 125I-labeled ZME-gelonin were identical in both the parental and resistant cells. A375-ZR cells were found to be more resistant to vincristine and doxorubicin than were parental cells. Both cell lines were almost equally sensitive to native gelonin, 5-fluorouracil (5-FU), cisplatin. melphalan, carmustine, interferon gamma (IFNgamma) and IFNalpha. In addition. both cell lines were equally sensitive to another gelonin antibody conjugate that binds to cell-surface, GD2 (antibody 14G2A). However, resistant cells were twice as sensitive to the cytotoxic effects of etoposide than were parental cells. Finally, a variety of agents were tested in combination with ZME-gelonin against A375-ZR cells in an attempt to identify agents to augment immunotoxin cytotoxic effects against resistant cells. The agents 5-FU, cisplatin, IFNgamma, IFNalpha, and etoposide were the most effective in augmenting the cytotoxicity of ZME-gelonin against resistant cells. These studies suggest that development of resistance to one immunotoxin does not cause development of cross-resistance to other gelonin immunotoxins. Further, specific biological response modifiers and chemotherapeutic agents may be effective in augmenting the effectiveness of immunotoxins and specifically targeting or reducing the emergence of immunotoxin-resistant cells.
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PMID:Cellular resistance to the antimelanoma immunotoxin ZME-gelonin and strategies to target resistant cells. 862 May 20


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