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)

The interferons are the first of a new class of biologic response modifiers that include, among others, the interleukins, colony-stimulating factors, erythropoietin, additional growth factors, and monoclonal antibodies. Interferons have exhibited important clinical activity in hematologic malignancies, lymphomas, and solid tumors. Specific diseases responding to interferons include hairy-cell leukemia (HCL), chronic myelogenous leukemia (CML), low-grade non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, multiple myeloma, superficial bladder carcinoma, malignant carcinoid, acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma, ovarian carcinoma, renal cell carcinoma, and malignant melanoma. The potentially antigenic nature of the recombinant interferons can result in the formation of antibodies. These antibodies have been associated with the abrogation of some of the clinical responsiveness of some patients treated with interferons. It is hoped that the controversy existing over the role of antibody formation in treatment efficacy can be resolved by prospective trials using standardized methodology in such areas as assay type, sampling time, route of drug administration, treatment schedule, cumulative dose, and duration of treatment.
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PMID:Biotherapy in clinical practice. 247 4

The effects and toxicities of interferon alfa are described, and the role of the pharmacist in making decisions and providing education about biologic response modifiers (BRMs) is discussed. Interferons have both direct antitumor activity and extensive effects on the immune system. Two recombinant interferon alfa products--interferon alfa-2a and interferon alfa-2b are available commercially. Indications in FDA-approved labeling for interferon alfa include the treatment of hairy-cell leukemia, acquired immunodeficiency syndrome-related Kaposi's sarcoma, and genital warts; however, it also is being used successfully against early chronic myelogenous leukemia, low-grade non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and previously untreated multiple myeloma. Other malignancies that respond to treatment with interferon alfa are malignant melanoma, ovarian carcinoma, and renal cell carcinoma. The toxic pattern of interferon alfa consists of flu-like symptoms, which are seen at all doses, on all schedules, and in virtually all patients. After repeated dosing, the chronic toxicities of anorexia, weight loss, and malaise and fatigue may develop. Myelosuppression, central nervous system toxicity, increased hepatic enzyme concentrations, nausea and vomiting, and cardiovascular toxicity also are possible. Serum neutralizing antibodies may be formed during therapy; this phenomenon may affect the clinical outcome. Numerous BRMs are being investigated for clinical use, and pharmacists must become conversant in the issues that surround these agents. Areas in which pharmacist involvement and knowledge are important include overall cost, product similarities and differences, dosing and scheduling, drug delivery systems, ways to minimize waste, adverse effects and their management, drug interactions, storage requirements, differences in production and purification techniques among manufacturers, and education of patients and staff.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biologic response modifiers: the interferon alfa experience. 248 96

1. The major functional role played by phosphorylation of plasma membrane proteins in the biological properties of tumor cells suggests that identification of protein kinases and their substrates will contribute to our understanding of the molecular basis of the malignant process and of the aberrant behavior of tumor cells. 2. The present study has investigated the phosphorylation of surface proteins of human tumor cells. Incubation of plasma membranes isolated from cultured human melanoma cells with [gamma-32P]ATP in the presence of Ca2+ and ethylene-bis-(oxyethylenenitrilo)-tetraacetic acid (EGTA) resulted in specific phosphorylation of serine and threonine residues on a 75kDa protein (pp75). 3. Neither Ca2+ or EGTA alone, nor any other divalent metal ion tested could induce phosphorylation of pp75. 4. The phosphorylation of pp75 was directly dependent upon the presence of non-ionic detergents, and was influenced by length of incubation and concentration ratio of Ca2+ and EGTA. 5. Incubation of isolated plasma membranes with [gamma-32P]ATP in the presence of Ca2+ and EGTA and immunochemical analysis by Western blotting with an anti pp75 xenoantiserum detected the pp75 in human melanoma, neuroblastoma, ovarian carcinoma and lymphoid T cells and fibroblasts but not in B-lymphoid cells, renal carcinoma cells, peripheral blood lymphocytes and splenocytes. 6. These results suggest the presence of a new class of plasma membrane bound protein kinases activated by chelated calcium and differentially expressed in normal and transformed human cells.
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PMID:Specific phosphorylation by calcium-EGTA complex of a 75 kDa human tumor plasma membrane protein (pp75). 250 5

Seventy-seven patients were treated with oral mitozolomide to assess the activity of this drug in melanoma, lung and ovarian cancer. Partial responses were seen in five of 18 evaluable patients with small cell lung cancer (SCLC) and three of 20 with melanoma. No activity was apparent in non small cell lung or epithelial ovarian cancer. The major toxicity was myelosuppression which necessitated reduction in the initial dosage from 115 to 90 mg/m2. However, even at this dose level, unpredictable WHO grade 4 toxicity occurred in non-pretreated patients. Thrombocytopenia was more common than leucopenia and eight patients required platelet transfusion for spontaneous or tumour-related haemorrhage. Myelotoxicity was considered responsible for two deaths and was a significant contributory factor in a further three. Non-haematological toxicity was minor. Thus, despite demonstrable activity in SCLC and melanoma, unpredictable myelosuppression is likely to preclude further assessment in combination chemotherapy regimes in these tumours.
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PMID:Phase II studies of mitozolomide in melanoma, lung and ovarian cancer. 254 29

Cytidine, a non-toxic endogenous nucleoside, was found unexpectedly to augment the cytotoxicity of a pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA) in human ovarian carcinoma cells. The PALA/cytidine synergy is confirmed here in other human tumor cells (T242 melanoma, HL60 promyelocytic leukemia and SKOV3 ovarian carcinoma) in the cytidine concentration range of 1-10 micromolar. The synergy was not observed in Chinese hamster ovary (CHO) cells. Exogenous uridine (5-50 microM) completely reversed the PALA/cytidine cytotoxicity in a concentration-dependent manner. Measurements of cellular ribonucleotide levels revealed that the PALA treated cells had reduced UTP and CTP pools (10% and 40% of control respectively); and the PALA/cytidine treated cells had elevated CTP and GTP levels while their UTP levels remained at 10% of control. Deoxyribonucleotide levels were unremarkable except for a slight elevation of dCTP in the PALA/cytidine treated cells. Uridine competitively inhibited radioactive cytidine transport into 2008 cells, which may explain its ability to antagonize the PALA/cytidine synergy. These results suggest that the ribonucleotide biosynthetic mechanism is the primary cellular target for PALA/cytidine activity, and that the ratio of ribonucleotides to each other is an important determinant of tumor cell viability. The use of non-cytotoxic nucleosides to augment the activity of antimetabolites may have clinical relevance in cancer therapy.
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PMID:Unexpected synergy between N-phosphonacetyl-L-aspartate and cytidine against human tumor cells. 271 48

A new fluorine-containing anthracycline derivative, ME2303, showed excellent antitumor activity against various experimental tumor models. The i.p. or i.v. administrations of ME2303 on Day 1 or on Days 1, 5, and 9 against i.p.-implanted L1210 leukemia cells rendered more than 50% of mice tumor free at wide ranges of nontoxic doses, whereas the incidence of cure obtained with Adriamycin (ADM) was less than that obtained with ME2303. ME2303 given i.p. or i.v. on Day 1 or Days 1, 5, and 9 was also effective against i.p.-implanted P388 leukemia cells, and higher incidences of cure were obtained than with ADM. ME2303 administered i.v. on Days 1, 8, 15, and 22 showed prominent antitumor activity against s.c.-implanted colon adenocarcinomas 26 and 38, Lewis lung carcinoma, B16 melanoma, and M5076 sarcoma. Against colon adenocarcinoma 26, ME2303 induced cure in 16 of 20 mice at doses of 35 to 71 mumol/kg, whereas no cure was observed with ADM. Significant growth inhibition of colon adenocarcinoma 38, Lewis lung carcinoma, B16 melanoma, and M5076 sarcoma cell lines was also observed at a dose of 18 to 106 mumol/kg. ME2303 was effective against human and murine multidrug-resistant cells in vitro. For example, human myelogenous leukemia K562 resistant to ADM (K562/ADM) was only 2.8-fold more resistant to ME2303, while the cells were 200-fold more resistant to ADM when the values for the concentration of drug required for 50% inhibition of cell growth were compared. ME2303 was also more effective than ADM against human leukemia CCRF-CEM resistant to vinblastine, human ovarian carcinoma A2780 resistant to ADM, human epidermoid carcinoma KB cells resistant to colchicine, and mouse leukemia P388 resistant to ADM and vincristine. Therapeutic effects were obtained in vivo against ADM- and, especially, vincristine-resistant P388 leukemia. ME2303 is one of the most interesting potential antitumor agents to be studied further.
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PMID:A fluorine-containing anthracycline (ME2303) as a new antitumor agent against murine and human tumors and their multidrug-resistant sublines. 279 Jul 78

Abnormal CA 15-3 antigen levels are found in the serum of most patients with advanced breast carcinoma. Elevations of this marker are less frequently seen in other malignancies. Circulating CA 15-3 levels might be useful in the differential diagnosis of the primary site of cancer. We studied the levels of CA 15-3 in 500 patients with different non-mammary cancers. Elevations of CA 15-3 (greater than 40 U ml-1) were observed in all types of epithelial malignancies, especially in ovarian (46%), respiratory (26%) and liver (30%) carcinomas. Abnormal values were observed in some patients with haematological malignancies and sarcomas, but not in melanoma or neurological tumours. CA 15-3 antigen levels correlated with the extent of non-mammary malignant tumours. Patients with locoregional cancer had a significantly smaller proportion of elevations of the antigen than those with distant metastases (12% versus 35%, P less than 0.001). In particular, elevated CA 15-3 levels were observed in 70% of patients with metastatic ovarian cancer. Liver involvement by cancer did not produce more elevations of CA 15-3 than metastases to other organs (32% versus 39%). Simultaneous determination of circulating CA 15-3 and CA 125 antigens in 58 patients with cancer of the ovary showed that CA 15-3 is elevated in some cases of ovarian carcinoma with non-elevated CA 125, and that CA 15-3 and CA 125 are distinct antigens. We conclude that circulating CA 15-3 antigen levels can be found elevated in virtually all types of cancer, particularly when distant metastases are present. Therefore, CA 15-3 levels should not be used in the differential diagnosis of the primary site in patients with metastatic malignancies of unknown origin. Evaluation of CA 15-3 levels may enhance the sensitivity of CA 125 in monitoring the course of ovarian carcinoma.
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PMID:Circulating CA 15-3 antigen levels in non-mammary malignancies. 293 Jun 93

This study was designed to define some biological aspects of cell suspensions, obtained by mechanical or enzymatic disaggregations, and to verify whether single cell suspensions are representative of original solid tumours. The study was performed on a series of 25 human solid tumours including breast carcinoma, ovarian carcinoma and malignant melanoma. A higher cell viability and a loss of aneuploid subpopulations, or a lower fraction of aneuploid cells, were observed in enzymatically-released samples than in samples obtained by the mechanical procedure. Moreover, the proliferative activity, which was generally similar for the cell suspensions obtained by the two disaggregation procedures, was always markedly lower in the cell suspensions than in solid samples from the same tumour. In conclusion, the results from this study indicate that many changes, such as selective release of cell populations from the tumour matrix, damage and destruction of aneuploid and proliferating cells can be induced to various extents by different disaggregation procedures.
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PMID:Implications of disaggregation procedures on biological representation of human solid tumours. 303 28

Purified, recombinant human gamma-interferon (rIFN-gamma) was tested at clinically achievable doses for direct and indirect antiproliferative activity against human tumor cell lines using a clonogenic assay. One-h treatment with rIFN-gamma showed direct dose dependent inhibition of tumor colony growth in cell lines established from human melanoma, myeloma, renal cell, and cervical cancers. Longer treatments resulted in suppression of ovarian and breast carcinoma clonogenicity. In order to test for indirect antiproliferative effects of rIFN-gamma, feeder cells were included in a separate agarose underlayer in the cloning assay. These feeder cells included mouse peritoneal macrophages, U-937 (human histiocytic lymphoma cell line), and adherent cells from human malignant ascites specimens. Colony growth of ovarian carcinoma and melanoma cell lines was stimulated by each of these feeder cell types. Cultures containing mouse peritoneal macrophages or U-937 cells showed the same antiproliferative responses to rIFN-gamma as did control cultures without feeder cells. In contrast, human adherent ascites cells (greater than 80% macrophages) became strongly inhibitory to tumor colony growth when treated with rIFN-gamma. These results suggest that human tumor associated macrophages may become tumoricidal under the influence of rIFN-gamma, producing a diffusable substance in agarose culture which causes the observed antiproliferative effects on tumor cells.
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PMID:Direct and indirect effects of human recombinant gamma-interferon on tumor cells in a clonogenic assay. 308 Feb 33

The capillary human tumor clonogenic cell assay (HTCA) has been shown to have important advantages over conventional HTCAs. In the present report, this promising novel HTCA was further optimized and characterized using 46 primary human tumor specimens, 6 human tumor cell lines (1 astrocytoma, 2 colon carcinomas, 1 melanoma), and 2 murine leukemias. Hydrocortisone, epidermal growth factor, heat-inactivated fetal calf serum, and horse serum were investigated for their ability to modulate tumor colony formation in the assay. Critical assay parameters that can affect tumor colony formation, namely, cell seeding density, agarose concentration, culture volume, capillary tube geometry, and capillary tube sealing, were also investigated. The results showed that serum (optimum concentration, 20%) was obligatory for tumor colony formation, and that both epidermal growth factor (50 ng/ml) and hydrocortisone (2.5 ng/ml), although supportive of colony growth, were not absolute requirements. Plating at 2.5-3 x 10(5) cells/ml in a culture volume of 50 microliters/capillary tube and an agarose concentration of 0.2% optimized colony formation (number, size, and distribution of colonies along the capillary tube) by primary human tumor cells. The cell lines generally formed colonies best at lower seeding densities and in lower culture volumes (30 microliters/tube). Colony formation was significantly better in unsealed than in sealed capillary tubes and growth was just as good, and in some cases, better in round capillary tubes than in square ones. Using ovarian carcinoma cells, the Cellscan prototype system was demonstrated as feasible for automated counting and evaluation of tumor colony growth in capillary tubes. A comparison of the capillary HTCA and the agar double-layer assay in Petri dishes produced a median plating efficiency of 0.18 for the capillary HTCA and 0.036 for the Petri dish method. The overall success rate was 77% for the former and 53% for the latter assay.
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PMID:Optimization and characterization of the capillary human tumor clonogenic cell assay. 325 71


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