UMLS:C0025202 - FACTA Search

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

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. We have studied here the recently identified transport-associated proteins, MRP and LRP, and the well-known drug resistance marker P-glycoprotein using a panel of 16 human melanoma cell lines and 71 benign and malignant melanocytic tissue samples. By flow cytometry and immunohistochemistry, expression of P-glycoprotein was not detectable on the protein level in the 10 cell lines analyzed, although by reverse transcriptase polymerase chain reaction, MDR-1 gene expression was demonstrated in 2 of 10 cell lines. In addition, immunohistology revealed P-glycoprotein expression in only 1 of 71 melanocytic lesions. In contrast, MRP was detected in a subset of melanoma cell lines by reverse transcriptase polymerase chain reaction and immunohistology (4 of 10). LRP expression was observed in 8 of 10 melanoma cell lines by immunochemistry and in 10 of 10 by reverse transcriptase polymerase chain reaction. Furthermore, MRP was detected immunohistologically in almost 50% of primary and metastatic melanoma specimens, although no significant differences were found between metastases taken before or after chemotherapy. Expression of LRP was detected in a subset of nevi with nevus cells exhibiting up to 25% positive LRP reactivity. In 13 of 21 primary melanomas and 23 of 37 metastases, more than 25% of tumor cells were stained by the LRP-56 monoclonal antibody. Particularly in the group of metastases with more than 50% of LRP-positive cells, 7 of 11 of the metastases had been previously exposed to chemotherapeutic drugs. Although the expression of membrane transport proteins may explain only the chemoresistance toward lipophilic, natural compounds and not resistance against alkylating agents, the lack of P-glycoprotein expression after chemotherapeutic treatment and the significant expression of MRP and LRP in melanoma cells provide first insights into the drug-resistant phenotype in melanoma. Additional studies analyzing the role of MRP and LRP in chemoresistance of melanoma are warranted.
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PMID:Membrane transport proteins associated with drug resistance expressed in human melanoma. 749 78

Previous data showing the correlation of multidrug resistance (MDR) and differentiation in tumor cell populations (Melloni et al. 1988; Stavrovskaya et al. 1990) suggest that: 1) isolation of MDR cells by cytostatic drugs leads to the selection of more differentiated cell variants and 2) in more differentiated cell variants the activity of MDR-related P-glycoprotein (Pgp) is more prominent than in less differentiated cells. Here we used human melanoma cell line mS and two variants selected from mS population: a) MDR variant of mS selected by colchicine (mS-0.5) and b) mS-trRAR/2--variant obtained by introduction of expressing retinoic acid receptor RAR-alpha cDNA into mS cell. The differentiation status, expression of MDR1 gene and Pgp functioning were compared in wild-type cells and mS variants. Electron microscopic examination of melanosomes showed that the mS-0.5 subline comprised more differentiating cells in the population than parental mS cultures and that these cells were at later stages of melanogenesis. The increase in the degree of differentiation in mS-0.5 population coincided with MDR1 gene overexpression, occurrence of Pgp molecules on the cell membrane and acceleration of Pgp-mediated Rhodamine 123 (Rh123) efflux. mS-trRAR/2, proved to be more differentiated than mS cells. The MDR1 mRNA level and Rh123 efflux were not elevated in mS-trRAR/2 cells, however, retinoic acid (RA) treatment increased both the degree of differentiation and Rh123 efflux in mS-trRAR/2 to a greater extent than in mS cultures. Thus, the data obtained in this study are in favor of the suppositions mentioned above. The mechanisms of coordinated alterations of differentiation and Pgp activity in MDR cells are discussed.
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PMID:Alterations of melanin synthesis in human melanoma cells selected in vitro for multidrug resistance. 758 Jan 2

Using an in situ kinase assay we have identified kinases that are elevated in some multidrug resistant cells. Kinases were detected by measurement of 32P incorporation in proteins that were renatured after being subjected to SDS-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membranes [Ferrell and Martin: J Biol Chem 264:20723-20729, 1989; Mol Cell Biol 10:3020-3026, 1990]. Kinases at 79, 84, and 92 kDa showed increased activity in the multidrug resistant human KB-V1 cells as compared to the sensitive parental KB-3-1 cells. The KB-V1 multidrug resistant cell line exhibited a 170 kDa membrane associated kinase activity that was not present in the parental drug sensitive line. The 170 kDa kinase activity was not affected by Ca++, phosphatidylserine, or cAMP, but was diminished after incubation in the presence of the kinase inhibitors staurosporine, K252a and KT5720. The 170 kDa kinase activity phosphorylated mainly threonine, with no evidence of tyrosine phosphorylation, and was not identical to either the multidrug resistance associated P-glycoprotein or the EGF receptor. Other multidrug resistant cell lines also showed elevated 170 kDa kinase activity, such as the human breast cancer MCF-7/Adr(R) and murine melanoma B16/Adr(R) cells, but the activity was not present in murine leukemia P-388 sensitive or multidrug resistant cells.
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PMID:Identification of a 170 kDa membrane kinase with increased activity in KB-V1 multidrug resistant cells. 769 26

The human melanoma cell line FEM-X was selected in multiple steps with VP-16 (etoposide) and an inhibitor of P-glycoprotein (Campain et al., 1993). The resulting clones, FVP1b and FVP3, are highly resistant to the nonintercalative epipodophyllotoxins and exhibit moderate levels of resistance to doxorubicin. The topoisomerase II activity present in crude nuclear extracts from mutant and wild-type cells is similar in amount and equally sensitive to VP-16. However, in live cells, the topoisomerase II from FVP1b and FVP3 is much less susceptible to drug-induced cleavable complex formation than is that from FEM-X. Using reverse transcription followed by the polymerase chain reaction (RT-PCR), we have cloned and sequenced the entire cDNA for topoisomerase II alpha from FEM-X and FVP3. The only sequence change unique to the cDNA from drug-resistant cells is a 3 bp deletion of nucleotide 1320-1322, resulting in a deletion of Ala429. Three FEM-X sublines of increasing resistance were tested, and the prevalence of the mutant RNA over wild-type increases in these cells in parallel with their resistance to VP-16. In FVP3, the most highly resistant line, expression of the wild-type allele is barely detectable. Analysis of genomic DNA shows that FEM-X is homozygous for the wild-type topoisomerase II alpha sequence and that each of the drug-resistant clones possesses both wild-type and mutant alleles. Although not definitive, these genetic results suggest that the deletion of Ala429 from topoisomerase II alpha makes the enzyme less susceptible to drug-induced cleavable complex formation and confers a growth advantage upon cells in the presence of VP-16.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A novel mutant topoisomerase II alpha present in VP-16-resistant human melanoma cell lines has a deletion of alanine 429. 772 83

Metastatic malignant melanoma is notoriously resistant to chemotherapeutic agents, but the exact mechanisms involved in this drug resistance are unknown. One recently defined major mechanism of multidrug resistance involves the overexpression of P-glycoprotein on cell membranes. In order to evaluate the significance of this putative drug efflux pump for chemoresistance of malignant melanoma, five different antibodies were employed to examine P-glycoprotein expression on tissue from 33 primary malignant melanomas and 35 metastases, before and after chemotherapy, using immunohistological techniques. The expression of P-glycoprotein was low on primary cutaneous melanomas (three of 33), and on metastases (one of 35). Normal tissue in and around the melanoma showed reactivity of endothelial cells, stromal cells and eccrine sweat glands with several antibodies tested. Chemotherapy with drugs commonly used in metastatic melanoma, including agents known to induce P-glycoprotein expression in other tumours (vindesine, cisplatin) had no effect on P-glycoprotein expression in human melanoma metastases. The high chemoresistance of human melanoma cells in vitro and in vivo is probably not mediated via P-glycoprotein, and other possible mechanisms involved will have to be explored in future studies.
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PMID:P-glycoprotein expression in primary and metastatic malignant melanoma. 774 45

We examined the in vitro effects of 8-chloro-adenosine 3':5'-monophosphate (8-Cl-cAMP), a reportedly stable, potent and site-selective analogue of cAMP, on the proliferation and sensitivity to doxorubicin (DXR) of two mouse cell lines, the B16 melanoma and Friend leukaemia, both as wild-type (B16, FLC) and DXR-resistant (B16/DXR, FLC/DXR) variants. The latter strains had characteristics of 'typical' multidrug resistance (MDR), including the over-expression of P-glycoprotein. Encouragingly, 8-Cl-cAMP affected almost equally the growth of the chemosensitive and chemoresistant variants of both cell lines. Its activity proved to be much more elevated on cells cultivated with fresh rather than heat-inactivated calf serum. In fact, the IC50 values for B16 and B16/DXR were about 4.7 microM in fresh serum and 215 microM in heat-inactivated serum; the IC50 values for FLC and FLC/DXR were about 12 microM in fresh serum and 70 microM in heat-inactivated serum. Furthermore, experiments with B16 showed that cotreatments with isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, or adenosine deaminase (ADA) greatly reduce the activity of 8-Cl-cAMP bringing it to comparable levels in fresh and heat-inactivated serum. These results indicate that the antiproliferative effects of 8-Cl-cAMP may be due principally to metabolites formed by the enzymic activities of the serum, most probably including 8-chloro-adenosine (8-Cl-adenosine), as suggested by other authors. Moreover, the dose-response curves and the IC50 values of the latter compound for the various cell lines were compatible with those observed for 8-Cl-cAMP in fresh serum. Finally, there was no evidence that 8-Cl-cAMP, either in the presence of fresh or heat-inactivated serum, or 8-Cl-adenosine may increase the sensitivity to DXR of the MDR variants of B16 melanoma and Friend leukaemia.
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PMID:Effects of 8-chloro-cyclic adenosine monophosphate on the growth and sensitivity to doxorubicin of multidrug-resistant tumour cell lines. 783 Nov 98

The intracellular distribution of the anthracyclinic antibiotic adriamycin in living cultured cells has been investigated by confocal microscopy. In human melanoma cells (M14), adriamycin was localized inside the nuclei. When adriamycin-treated M14 cells were allowed to recover in drug-free medium, a complete efflux of the drug from the nucleus was revealed. In recovered cells, a weakly fluorescent signal was observed in the perinuclear region. When M14 cells were recovered in a medium containing colcemid, a microtubule depolymerizing agent, the drug transport from the nucleus to the cell periphery appeared to be inhibited, suggesting that the microtubule network is strongly involved in drug transport mechanisms. In multidrug-resistant (MDR) cells the intracellular location of adriamycin was shown to be noticeably different from that of the parental wild-type cells. In particular, in resistant human breast carcinoma cells (MCF-7), adriamycin appeared to be exclusively located within the cytoplasm whereas the nuclei were shown to be completely negative. When adriamycin treatment was performed in association with MDR revertants, such as Lonidamine (inhibitor of the energy metabolism) or verapamil (inhibitor of the P-glycoprotein efflux pump), a marked enhancement of the cytoplasmic signal was observed in resistant cells. Under these conditions, adriamycin appeared concentrated in the perinuclear region, but the nuclei were still negative. Confocal microscopy proved to be a very useful method for the study of the intracellular transport of fluorescent substances, such as anthracyclinic antibiotics, and for the investigation of the multidrug resistance phenomenon in tumour cells.
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PMID:Intracellular localization of the antitumour drug adriamycin in living cultured cells: a confocal microscopy study. 786 63

We report on the antiproliferative effects that interleukin-1 alpha (IL-1) or TNF-alpha (TNF) in combination with doxorubicin (DXR) exert on DXR-sensitive (B16 melanoma, Friend, K562 and CCRF/CEM leukemias) and -resistant (B16-DXR, FLC-DXR, K562-DXR) cell lines in vitro. Multidrug resistance (MDR) of the latter lines entails cross-resistance to vincristine and overexpression of P-glycoprotein. Il-1 showed only a very marginal growth inhibitory activity and the effects of its combination with DXR were essentially additive in all the cell lines, except in chemosensitive B16, where a slight synergism occurred. TNF demonstrated greater antiproliferative activity in the MDR B16 and Friend tumors than in their parent variants. The combination of TNF and DXR produced synergistic growth inhibition in B16, K562 and, particularly, also in the MDR sublines of these two tumors. In addition, TNF and DXR induced synergistically erythroid differentiation in K562 and multidirectional differentiation in K562-DXR. The synergism was critically schedule-dependent in that it was achieved only when DXR application preceded or was simultaneous with that of TNF. Finally, TNF did not modify drug accumulation and retention in the cells. Our present findings stress especially the fact that DXR and TNF may exert useful antitumor synergism even in MDR lines; however, it is not likely that their interaction will occur at the specific MDR process level.
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PMID:Combined activity of interleukin-1 alpha or TNF-alpha and doxorubicin on multidrug resistant cell lines: evidence that TNF and DXR have synergistic antitumor and differentiation-inducing effects. 787 95

Certain N-alkylated analogues of the natural polyamine spermine, such as N1,N11-diethylnorspermine (DENSPM), rapidly deplete intracellular polyamine pools by down-regulating the biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, and by potently up-regulating the polyamine catabolizing enzyme, spermidine/spermine N1-acetyltransferase. On the basis of previously reported antitumor activity in human tumor xenograft model systems, DENSPM is currently undergoing Phase I clinical trials against human melanoma and other solid tumors. The antiproliferative activity of this analogue against the multidrug resistance (MDR) phenotype was examined in three MDR sublines of human melanoma RPMI-7932 cells, which were shown to be 2-to 10-fold resistant to classical MDR agents. These MDR lines had been separately derived using different selecting agents (Lemontt et al., Cancer Res., 48: 6344-6353, 1988). Subline functional resistance due to P-glycoprotein was confirmed by decreased retention of rhodamine 123 relative to parent cells as detected by flow cytometry. Although the three sublines were 2- to 10-fold less sensitive than the parent line to classical MDR-type agents, they were found in dose-response studies to be significantly more sensitive to DENSPM than the parent line. In addition, they showed a distinct cytotoxic response after a 48-h treatment with 10 microM DENSPM, which was not apparent in the parent line. Growth sensitivity of the sublines to the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, or the S-adenosylmethionine decarboxylase inhibitor, CGP-48664, was found to be similar to parent cells. The ratio of the key biosynthetic enzyme activities for ornithine decarboxylase and S-adenosylmethionine decarboxylase was found to be 3.5- to 5-fold higher in all three sublines, due mainly to increases in the former enzyme. This imbalance produced unusually high putrescine pools. Although DENSPM down-regulation of decarboxylase activities and potent up-regulation of spermidine/spermine N1-acetyltransferase activity occurred similarly in both parent and variant lines, polyamine depletion was greater in the variant lines. Collateral sensitivity of the MDR sublines to DENSPM is partially attributable to the finding that analogue (and spermidine) uptake in the sublines was about 2-fold higher (after 2 h) than in the parent cells. The presence of disturbances in polyamine homeostasis and increased sensitivity to DENSPM in three independently selected cell line variants suggests that they may be generally associated with the MDR phenotype in human melanoma and possibly other tumor cells. The collateral sensitivity of human melanoma MDR variants to DENSPM represents a possible therapeutic indication which should be considered during the ongoing clinical evaluation of this drug.
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PMID:Collateral sensitivity of human melanoma multidrug-resistant variants to the polyamine analogue, N1,N11-diethylnorspermine. 795 23

Metastatic malignant melanoma is considered a chemotherapy-refractory malignancy. A few previous studies have delivered contradictory results regarding the presence and functionality of P-glycoprotein (P-gp), a transmembranous protein associated with the classical multidrug resistance (cMDR), in malignant melanoma. Therefore we have investigated this issue on 33 cell lines established from primary and metastatic lesions of human malignant melanoma, comparing different cMDR detection methods. Immunocytochemically 33% of the cell lines stained positive for P-gp. The data correlated with those of a P-gp-radioimmunometric (antibody-binding) assay. When RT-PCR was used for MDR-1 mRNA determination, 76% of the melanoma cell lines scored positive. Slot-blot analysis was seen to be less sensitive than RT-PCR. Results from the functional P-gp assays, using daunomycin (DM) as MDR-substrate, showed no influence of P-gp expression on drug accumulation and cytotoxicity. However, the cMDR-modifier verapamil (VP) significantly increased both parameters in those melanoma cells with the highest P-gp levels. We conclude that cMDR is apparently not the decisive but probably a complementary protective mechanism against toxic agents in malignant melanoma.
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PMID:Intrinsic MDR-1 gene and P-glycoprotein expression in human melanoma cell lines. 796 Feb 46

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