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 occurrence of multidrug resistance (MDR) decreases the clinical utility of several anticancer agents, including doxorubicin (DOX). A transmembrane efflux pump, P-glycoprotein (P-gp), is frequently implicated in the development of MDR in tumor cells. Dipyridamole (DP), a clinically used antiplatelet drug, enhances the cytotoxicity of the anticancer drugs affected by MDR. Although this aspect has been studied extensively in cell culture models, the effectiveness of DP to overcome multidrug resistance has not been investigated using in vivo models of multidrug-resistant solid tumors. Therefore, the objective of this study was to evaluate the role of DP in the reversal of resistance to DOX in tumor-bearing mice in the context of its anti-MDR activity in vitro. For this purpose, drug-sensitive murine melanoma cells (B16V) and their DOX-selected MDR variant, B16VDXR cells, were used. In vitro, the reversal of DOX resistance of B16VDXR cells by DP was determined using clonogenic assays, and the influence of DP on the transport of DOX was evaluated by measurement of steady-state accumulation as well as efflux of DOX in B16VDXR cells. Antitumor activity of different treatments was assessed by monitoring tumor growth. Pharmacokinetics of DOX, with or without DP, were evaluated in C57BL/6 mice bearing B16V or B16VDXR tumors. DP produced a 6.4-fold reversal of resistance to DOX in vitro; this was accompanied by an increase (3.6-fold) in the steady-state intracellular accumulation of DOX and a marked reduction in the efflux of DOX from B16VDXR cells. Furthermore, a linear correlation was observed between the EC50 values and the steady-state intracellular levels of DOX in the multidrug-resistant cells. In the in vivo experiments, similar growth patterns were seen for the DOX alone and the DOX+DP groups for B16V tumors. The results with B16VDXR tumors were in sharp contrast. The DOX+DP treatment caused a significant delay in the growth of B16VDXR tumors compared to treatment with DOX alone or controls. DP did not alter the plasma pharmacokinetics of DOX in C57BL/6 mice but resulted in a significant increase in the intratumoral accumulation of DOX.
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PMID:Reversal of doxorubicin resistance in multidrug resistant melanoma cells in vitro and in vivo by dipyridamole. 922 48

We determined whether tumour size in vivo and cell density in vitro modulate the expression of the mdr-1 gene in B16 melanoma cells. Cells were injected subcutaneously into syngeneic mice. Small (5 mm in diameter) and large (15-20 mm in diameter) tumours were harvested. Tumour cells from small subcutaneous tumours exhibited higher levels of mdr-1 mRNA (measured using Northern blot and in situ hybridization) and P-glycoprotein (P-gp) (measured using immunohistochemistry and fluorescent activated cell sorter analysis), as well as greater. In vitro resistance to doxorubicin (DXR) than cells from large subcutaneous tumours. immunohistochemical studies using an antibody against proliferating cell nuclear antigen revealed that the small subcutaneous tumours contained a larger fraction of proliferating cells than the large tumours. To determine whether cell proliferation correlated with expression of mdr-1, we plated B16-F10 cells to yield sparse and confluent monolayer cultures. The levels of mdr-1 mRNA and P-gp and resistance to DXR and phosphotyrosine activity were higher in the sparse cultures than in the confluent cultures. These results demonstrate an intratumoral heterogeneity for the expression of mdr-1 that directly correlates with intratumoral heterogeneity for cell division.
Melanoma Res 1997 Aug
PMID:Intratumoral heterogeneity for and epigenetic modulation of mdr-1 expression in murine melanoma. 929 77

The intracellular location of the MDR1 gene product, known as P-glycoprotein (P-gp), has been detected by flow cytometry in 3 stabilized human melanoma cell lines which had never undergone cytotoxic drug treatment and did not express P-gp on the plasma membrane. In addition, MDR1 mRNA expression was revealed by RT-PCR in the same cell lines. Immunofluorescence microscopy, performed by using the same 2 monoclonal antibodies (MM4.17 and MRK-16) as employed in the flow-cytometric analysis, revealed the presence of P-gp intracytoplasmically, in a well-defined perinuclear region. Double immunofluorescence labelling and immunoelectron microscopy strongly suggested the location of the transporter molecule in the Golgi apparatus. The same observations have been obtained on a primary culture from a metastasis of human melanoma. Analysis of the expression of another membrane transport protein, the multidrug-resistance-related protein (MRP1), showed that it was present in the cytoplasm of all the melanoma cell lines examined. MRP1 also showed Golgi-like localization. The study by laser scanning confocal microscopy on the intracellular localization of the anti-tumoral agent doxorubicin (DOX) during the drug-uptake and -efflux phases, indicated the Golgi apparatus as a preferential accumulation site for the anthracyclinic antibiotic. P-gp function modulators (verapamil and cyclosporin A) were able to modify DOX intracytoplasmic distribution and to increase drug intracellular concentration and cytotoxic effect in melanoma cells. On the contrary, MRP1 modulators (probenecid and genistein) did not significantly influence either DOX efflux and distribution or the sensitivity of melanoma cells to the cytotoxic drug.
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PMID:Detection of P-glycoprotein in the Golgi apparatus of drug-untreated human melanoma cells. 950 34

The goal of our study was to obtain direct evidence of co-ordinated regulation of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) and differentiation in tumour cells and to study some signalling pathways involved in joint regulation of these two cell phenotypes. The sublines of human melanoma (mS) and hepatoma (human HepG2 and rat McA RH 7777) cell lines were obtained by retroviral infection of the wild-type cells with the cDNA of the human retinoic acid receptor alpha (RAR alpha). The resulting sublines stably overexpressed exogenous RAR alpha gene. The infectants became more differentiated than the parental cells as determined by a decrease in the synthesis of the embryo-specific alpha-fetoprotein in HepG2 and McA RH 7777 hepatoma cells and by an increase in melanin synthesis in mS cells. The differentiation of human cells was accompanied by an increase in the amounts of MDR1 mRNA but not by an increase in P-gp activity as a drug transporter, in contrast, in the rat RAR alpha overexpressing cells P-gp functional activity was elevated. Treatment with cytotoxic drug (colchicine) or retinoic acid (RA) resulted in a slight increase in P-gp activity in the parental and RAR alpha-infected melanoma cells, whereas the increase in P-gp function in the infected hepatoma cells (both human and rat) was very prominent. Thus, we provide new evidence that cell differentiation caused by the overexpression of the gene participating in the differentiation programme leads to overexpression of MDR1 gene and drug resistance and that this effect is tissue and species specific. These data imply that the activation of the RA-controlled signalling pathway up-regulates MDR1 gene expression.
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PMID:Influence of exogenous RAR alpha gene on MDR1 expression and P-glycoprotein function in human and rodent cell lines. 966 38

Water-insoluble camptothecin (CPT) congeners are rapidly establishing themselves as promising anticancer drugs. In vitro, they have exhibited: (a) insensitivity to elevated levels of P-glycoprotein that confers multidrug resistance; (b) selective killing of malignant cells traversing the S-phase of the cell cycle, while leaving viable normal cells, which either are arrested at the S-G2 boundary or continue to divide; (c) no cross-resistance with several other anticancer drugs; and (d) potentiation or enhancement of cytotoxicity when appropriately used in combination with tumor necrosis factor, ionizing radiation, and hyperthermia. In addition, development of cell resistance to water-insoluble CPT congeners in vitro is accompanied by increased sensitivity to other anticancer drugs. Furthermore, water-insoluble CPT congeners have exhibited an unprecedented activity against a wide variety of human tumors xenografted in nude mice by inhibiting growth and inducing regression of carcinomas of the lung, breast, ovary, colon, stomach, pancreas, and prostate, as well as malignant melanoma, lymphoma, and leukemia. More importantly, oral administration of the water-insoluble CPT congeners in clinical studies with cancer patients makes other route(s) of administration unnecessary.
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PMID:Preclinical studies of water-insoluble camptothecin congeners: cytotoxicity, development of resistance, and combination treatments. 981 17

Malignant melanoma is considered to be a chemotherapy-refractory tumour and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. The cellular resistance mechanisms involved in melanoma chemoresistance have not yet been elucidated. Melanoma-derived cell lines are often markedly chemoresistant. Using the in vitro soft agar culture system to predict tumour cell sensitivity in well-established human melanoma cell lines, a high degree of resistance against all the cytostatic agents studied has been reported, suggesting the presence of intrinsic cellular resistance mechanisms. The relevance of the well-defined resistance mechanisms mediated by P-glycoprotein, multidrug resistance-associated protein (MRP), the glutathione/glutathione S-transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras oncogene has recently been implicated in melanoma resistance to cisplatin, both in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which are already involved in the chemoresistance of haematological and solid malignancies, is beginning to be better elucidated. The finding that many chemotherapeutic agents can kill susceptible cells through the apoptosis pathway provides new molecular insight into chemoresistance mechanisms and suggests that apoptosis and/or resistance to apoptosis of melanoma cells should be investigated to better clarify the mechanism of melanoma chemoresistance.
Melanoma Res 1999 Feb
PMID:The chemoresistance of human malignant melanoma: an update. 1033 34

A comparison of the expression of P-glycoprotein (Pgp) was performed in two forms of hamster transplantable melanomas of common origin, but differing in growth rates and levels of differentiation. The expression of P-glycoprotein in plasma membranes of these two forms of melanomas was estimated by the western blot analysis and the transport activity of the Pgp compared by flow cytometry. It was observed that a spontaneous alteration in the original melanotic melanoma leading to a formation of the amelanotic form characterized by higher growth rate, greater anaplasticity and leading to the animals' death after a shorter time from inoculation, was accompanied by a decrease in the Pgp expression and activity, due to simultaneous appearance of a small population of amelanotic cells with high Pgp expression and activity, and disappearance of this activity from the major population. It is possible, that the activity of Pgp in the melanoma cell membranes reflects the degree of cell differentiation.
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PMID:Diversity of the plasma membrane properties of transplantable hamster melanomas with regard to the expression of P-glycoprotein. 1048 49

Cutaneous malignant melanoma is a life-threatening cancer with poor prognosis due to a high metastasis potential. The main obstacle in treatment of metastatic melanoma is the resistance to chemotherapy. Recent studies indicated that apoptosis is a common mechanism of action for various cytotoxic agents. As p53 plays an important part in apoptosis, we investigated the role of p53 in chemosensitivity of melanoma cells. Previously, we found that melanoma cell lines containing wild-type p53 have significantly higher response rates to chemotherapy than cell lines with a mutant p53 gene. To confirm the role of p53 in melanoma chemosensitivity further, we transfected an expression vector, pED1, which carries a mutant p53 gene, into a wild-type p53 melanoma cell line, MMAN. We examined the effect of mutant p53 on camptothecin-induced apoptosis and the expression of genes which are known to be involved in apoptosis or drug resistance, such as bcl-2, bax, bak, p21waf1, and P-glycoprotein. Our results indicate that overexpression of the mutant p53 increased the growth rate of MMAN cells, reduced the sensitivity to camptothecin, and lowered drug-induced apoptosis by 2-3-fold. Flow cytometry indicated that the camptothecin-induced apoptosis is not associated with G1 arrest. Furthermore, camptothecin treatment reduced bcl-2 and P-glycoprotein expression in wild-type p53 MMAN cells, but not cells overexpressing mutant p53. These results demonstrate that p53 mutational status is a determinant of melanoma chemosensitivity. p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy.
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PMID:p53-dependent apoptosis in melanoma cells after treatment with camptothecin. 1069 11

Melanoma cells exhibit, both in vivo and in vitro, intrinsic drug resistance to various chemotherapeutic agents. Cultured human melanoma cells (M14) intrinsically express significant amounts of multidrug resistance-related protein (MRP1) and P-glycoprotein (P-gp) in the Golgi apparatus, but do not express these drug transporters on the plasma membrane. A panel of multidrug resistant (MDR) melanoma cell lines (M14Dx), showing different degrees of resistance to doxorubicin (DOX), were isolated. In M14Dx lines, the appearance of surface P-gp, but not of MRP1 or lung resistance related protein (LRP), occurred in cells grown in the presence of DOX concentrations higher than 60 nM. Furthermore, P-gp levels appeared to be dose-dependent. Flow cytometry, laser scanning confocal microscopy and cytotoxicity studies demonstrated that the activity of the drug extrusion system was related to both surface P-gp expression and resistance to DOX. In conclusion, P-gp, but not MRP1 or LRP, might play a pivotal role in the pharmacologically-induced MDR phenotype of melanoma cells.
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PMID:Induction of P-glycoprotein expression on the plasma membrane of human melanoma cells. 1095 45

In the study described here we investigated the possibility of an association between the aggressiveness of melanoma and multidrug resistance phenotype by analyzing the expression and activity of P-glycoprotein (Pgp) in two genetically related transplantable hamster melanomas--a melanotic (Ma) and an amelanotic (Ab) form --which differed in aggressiveness and metastatic potential. Flow cytometric analysis of Pgp activity (using a verapamil-sensitive rhodamine R123 exclusion test) as well as Western blotting of cellular lysates showed its preferential (although not very marked) expression in the Ab melanoma cells. The Ab melanoma cells also exhibited a higher proportion of tumor-infiltrating lymphocytes (TIL), mostly of T cell phenotype, that may have reflected a higher immunogenicity of the tumor. In conclusion, Pgp activity appeared to be associated with less-differentiated more aggressively metastasizing melanoma (the Ab variant) although its role in maintaining this phenotype remains to be established.
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PMID:Expression and activity of P-glycoprotein in transplantable hamster melanomas. 1096 60


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