Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired or spontaneous resistance is a major clinical problem in the treatment of cancer. Low levels of MDR gene expression or P-glycoprotein have been correlated with a high level of drug resistance in vitro and a poor response to chemotherapy in some tumors. A strong correlation between MDR mRNA, P-glycoprotein levels and degree of drug resistance has not been found in several resistant model tumor cell lines. In some cell lines at low and high level of resistance different mechanisms seem to be involved.
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PMID:Studies on low-level MDR cells. 776 28

It was the aim of this study to compare drug-resistant sublines of the murine P388 in relation to resistance markers, the resistant phenotype and immunogenicity. Resistance to drugs either belonging to the MDR type (Doxorubicin, Vincristine, Mitoxantrone) or to the non-MDR type (Methotrexate) was generated in vivo in order to mimic the clinical situation. All resistant sublines expressed the mdr1 gene and the p-glycoprotein determined on m-RNA level or immunohistochemically, while no expression was registered in the parent P388. The rhodamine 123 fluorescence as marker for the energy dependent drug efflux pump was decreased only in the MDR-sublines, while the parent P388 and the Methotrexate-resistant line retained 100% or 90% of the dye, respectively. This indicates that the rhodamine efflux is a more function-related marker for MDR than the mdr1 gene and the pgp. The in vivo characterization of the sublines as regards their sensitivity to cytostatics revealed a clear-cut cross-resistance to MDR drugs in the MDR-lines, while the Methotrexate resistant subline was only cross-resistant to Cytarabine. In each resistant subline collateral sensitivity to certain but different cytostatics was observed. Experiments to overcome resistance by concomitant treatment with the modulators Nifedipine, Verapamil, Cyclosporin A and Chloroquin led to only limited success. The sublines P388/Mitox, P388/Vinc and P388/MTX developed immunogenicity which was never registered in the original P388. Vaccination with lethally irradiated drug-resistant cells resulted in a substantial rejection of viable tumor cells of the same line. With the P388/Mitox and P388/Vinc also an over-cross immunization was possible. This generation of immunogenicity as a concomitant characteristic of resistance should be considered as therapeutic potential also in the treatment of clinical cancer.
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PMID:Characterization of four drug-resistant P388 sublines: resistance/sensitivity in vivo, resistance-and proliferation-markers, immunogenicity. 784 40

The objective of the experiments reported in this paper was the identification of promising anthracycline analogs on the basis of lack of cross-resistance against tumor cells presenting either P-glycoprotein multidrug resistance (Pgp-MDR) or the altered topoisomerase multidrug resistant (at-MDR) phenotype. Differently modified anthracycline analogs known to be active against MDR cells were assayed in vitro against CEM human leukemic cells, and the sublines CEM/VLB100 and CEM/VM-1 exhibiting respectively the Pgp-MDR and the at-MDR phenotype. Two classes of molecules, in which the -NH2 group in C-3' position is substituted with a morpholino, methoxymorpholino (morpholinyl-anthracycline), or an alkylating moiety, present equivalent efficacy in the drug-sensitive and the two drug-resistant sublines. These results indicate that such molecules may exert their cytotoxic effect through a mode of action different from that of "classical" anthracyclines and is not mediated through topoisomerase II inhibition. Both molecules represent novel concepts in the field of new anthracyclines derivatives.
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PMID:Growth-inhibitory properties of novel anthracyclines in human leukemic cell lines expressing either Pgp-MDR or at-MDR. 786 Feb 37

Multidrug resistance represents a major obstacle in the successful therapy of neoplastic diseases. Studies have demonstrated that this form of drug resistance occurs in cultured tumor cell lines as well as in human cancers. P-glycoprotein appears to play an important role in such cells by acting as an energy-dependent efflux pump to remove various natural-product drugs from the cell before they have a chance to exert their cytotoxic effects. Using the tools of molecular biology, studies are beginning to reveal the true incidence of multidrug resistance, as mediated by the MDR1 gene, in the clinical setting. It has been demonstrated, at least in the laboratory, that resistance mediated by P-glycoprotein may be modulated by a wide variety of compounds, including verapamil and cyclosporine A. These are compounds which, by themselves, generally have little or no effect on the tumor cells, but when used in conjunction with antineoplastic agents act to decrease, and in some instances eliminate, drug resistance. The mechanism(s) by which these agents act to reverse resistance is not fully understood. Clinical trials to modulate P-glycoprotein activity are now under way to determine whether such strategies will be feasible. The detection of the P-glycoprotein in patient samples is very important in the design of these studies, as it appears that drug-resistant cells lacking P-glycoprotein will be unaffected by agents such as verapamil. Clinical studies are needed in which patients are stratified into chemotherapy protocols based on levels of MDR1 mRNA or P-glycoprotein expression in the primary tumors. Several research areas have been identified that are important to the transfer of the discovery of the MDR1 gene and its protein product from the research laboratory to the clinical environment. There is an immediate need for comprehensive information on the prevalence and levels of expression of the human MDR genes and their protein products in human organs and tissues. Data are needed on P-glycoprotein levels in specific subpopulations (e.g., according to age, sex, race, and diet), and the study of the heterogeneity and variability of expression of P-glycoprotein in normal human tissues should be given high priority. Since early studies have indicated some successes in identifying patients with classic multidrug resistance who might be responsive to chemosensitization, it can be anticipated that clinical research will accelerate in this area. The next wave of clinical studies will provide clinical investigators with opportunities to develop and evaluate P-glycoprotein tests and correlate test results with clinical outcomes.
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PMID:Multidrug resistance in the laboratory and clinic. 787 70

Antibiotic C3368-B (CB), identified as 3,9-dihydroxy-1-methoxy-7-methylanthraquinone, is produced by a fungus strain, Chrysosporium verrucosum Tubaki, isolated from a soil sample collected from Antarctica. CB was found to be a highly-active nucleoside transport inhibitor. By radiolabelled nucleoside assay, CB was shown to markedly inhibit thymidine and uridine transport in Ehrlich carcinoma cells, with IC50 values of 7.5 and 9.6 mumol.L-1 respectively. CB showed fairly low cytotoxicity to tumor cells. The IC50 values for epidermoid cancer KB cells and hepatoma BEL-7402 cells in clonogenic assay was 77 and 69 mumol.L-1. At relatively noncytotoxic concentrations, CB markedly enhanced the cytotoxicity of methotrexate, 5-fluorouracil, mitomycin C against KB cells and BEL-7402 cells. CB was also found to partly reverse the multi-drug resistance to vincristine and actinomycin D in leukemia L1210/MDR cells. The IC50 values were reduced by 4.9-fold (1.75 to 0.36 mumol.L-1) for vincristine and 3.3-fold (0.39 to 0.12 mumol.L-1) for actinomycin D. These results suggest that CB, as a newly-found nucleoside transport inhibitor, may be potentially useful in cancer chemotherapy.
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PMID:[A fungus-derived novel nucleoside transport inhibitor potentiates the activity of antitumor drugs]. 790 May 36

Acquired resistance to chemotherapeutic drugs by tumor cells is an important obstacle to effective therapy of human malignancy. These resistance cell lines originated from human or rodent have been characterized by increased expression of MDR (Multidrug-resistance) gene and P-glycoprotein which plays as efflux pump of drugs from cells. These multidrug-resistance sublines also have been reported increased activities of protein kinases and glutathione S-transferase-pi. Although there have been extensive biophysical and biochemical characterization of the differences between parental lines and MDR tumor cell sublines, morphologic observations have been limited. In this study, filamentous cytoskeletons which involve many biological phenomena such as maintenance of cell morphology, mitosis, cellular movement, transport, and adhesion, were observed by confocal laser microscopy. To compare the expression of each cytoskeletons, fluorescent intensities of cells stained for each cytoskeletons were measured by confocal laser microscopic system. Utilizing this methodology, higher microtubular expression was observed in HL-60/ADR and K562/ADR than in their parental lines, but no significant differences of actin and vimentin were observed. Phosphorylation by protein kinases has been established as a key factor in the regulation of cytoskeletal function. But little is known about the role of protein phosphorylation in cytoskeletal function. Since increased activities of PKC and PTK were detected in HL-60/ADR, the effect of PKC inhibitor, staurosporine (STR), or PTK inhibitor, genistein (GNS), on cell growth was detected. STR and GNS reduced the resistance to Adriamycin in HL-60/ADR. Furthermore, STR and GNS disrupted the filamentous structure of microtubules in HL-60/ADR, and suppressed the expression of microtubules to 37%, and 49%, respectively. In contrast, PKC activator, phorbol ester (TPA), caused stronger microtubular assembling in HL-60/ADR, and increased the expression of microtubules to 134%. Resulting from this study, it is likely that acquired MDR of HL-60 and K562 was associated with increased expression of microtubules, and microtubular assembling or disassembling was considered to be regulated in part by PKC and PTK.
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PMID:[Features of filamentous cytoskeletons in acquired multidrug-resistance of HL-60 human leukemia cell line]. 790 88

Intratumoral heterogeneity was studied in human breast cancer by examining separate tumor lesions of individual patients. Tumor samples were obtained from each patient by fine-needle biopsies from 2 to 4 separate tumor lesions. We used a semi-quantitative PCR to distinguish between samples with gene amplification and single gene copy samples. Five genes were analyzed in each biopsy: MDR-1, dihydrofolate reductase, thymidylate synthase, c-erb-B2 and int-2. Three groups of patients were examined: those awaiting initiation of treatment; those receiving first-line endocrine therapy; and those receiving second-line endocrine treatment. A pattern of intratumoral heterogeneity for gene amplification was clearly apparent. The frequency of amplification was lowest before initiating therapy and highest in patients receiving second-line treatment (p = 0.023).
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PMID:Intratumoral heterogeneity for amplified genes in human breast carcinoma. 791 34

In several multidrug resistant tumor cell lines without overexpression of P-glycoprotein (non-Pgp MDR), a decreased accumulation of drugs has been shown to contribute to resistance. We have recently reported that daunorubicin (DNR) accumulation was decreased in the multidrug resistance-associated protein overexpressing GLC4/ADR non-Pgp MDR small cell lung cancer cell line due to an enhanced energy-dependent efflux which could be inhibited by the isoflavonoid genistein. The purpose of this work was 2-fold: (i) to investigate the mechanism by which genistein inhibits the DNR efflux in the GLC4/ADR cells; and (ii) to characterize the dependence of DNR transport on ATP concentration in intact GLC4/ADR cells. The active transport of DNR in GLC4/ADR cells appeared to be a saturable process with an apparent Km of DNR of 1.4 +/- 0.4 microM. Genistein increased the apparent Km value of DNR, suggesting that this agent is a competitive inhibitor of DNR transport. These data provide additional evidence that energy-dependent DNR transport in GLC4/ADR cells is a protein-mediated process. In addition, genistein decreased cellular ATP concentration in a dose-dependent manner in sensitive as well as in resistant cells. Marked inhibition of DNR transport activity in intact GLC4/ADR cells was found when cellular ATP concentration was decreased below 2 mM by sodium azide or 2-deoxy-D-glucose. Thus, since DNR transport in intact GLC4/ADR is already inhibited at modest cellular ATP depletion, a limitation in ATP supply might open ways to make MDR cells more susceptible to drug toxicity.
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PMID:Competitive inhibition by genistein and ATP dependence of daunorubicin transport in intact MRP overexpressing human small cell lung cancer cells. 794 6

The benzoquinonoid ansamycin antibiotics, geldanamycin and herbimycin A, are potent cytotoxins against tumor cells in vitro. We have examined the mechanism of their in vitro cytotoxicity against human breast adenocarcinoma (MCF-7) cells and we have found that multidrug-resistant MCF-7/ADRR cells that exhibit the MDR phenotype and the overexpression of P-170-glycoprotein, were cross-resistant to geldanamycin and herbimycin A. Verapamil, which binds competitively with P-170-glycoprotein, enhanced geldanamycin cytotoxicity 12-fold only in resistant cells, suggesting that geldanamycin may interact with the drug efflux protein. Geldanamycin and herbimycin A, like adriamycin, were reductively activated by the NADPH-cytochrome P450-reductase and formed reactive .OH. The formation of .OH was significantly lower in resistant cells. In contrast to adriamycin, the formation of .OH was unaffected by the addition of DNA, indicating that a DNA-complexed drug was redoxactive and may, therefore, may be more effective in killing tumor cells at the DNA level. These observations indicate that both the decreased free radical formation and interactions with P170 glycoprotein may be important in geldanamycin and herbimycin A resistance in multidrug resistant human breast tumor cells.
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PMID:Free radical formation by ansamycin benzoquinone in human breast tumor cells: implications for cytotoxicity and resistance. 798 24

A 75-year-old man was admitted to our hospital on June 1st, 1993, because of nasal obstruction, epistaxis, fever, night sweats and weight loss. Examination disclosed a 2-cm white necrotic mass in the nasal septum, and a biopsy disclosed non-Hodgkin's lymphoma, diffuse, mixed-type. Imprint smears showed cytoplasmic azurophilic granules in the tumor cells. Dense granules were demonstrated by electron microscopy. The tumor cells were CD1-2+3-4-7+8-16+56+57-, and T cell receptor genes were in germline configuration. NK activity against K562 was strongly positive. Based on morphologic, phenotypic, immunogenotypic, and cytotoxic findings, the tumor cells seemed to be derived from activated NK cells. Because the tumor cells were positive for the EB virus and CD21 antigen, EB virus seemed to have infected CD21-positive NK cells and transformed them. MDR P-glycoprotein was also positive. This finding may explain why nasal lymphomas are resistant to chemotherapy and have a poor prognosis.
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PMID:[Nasal NK-cell lymphoma]. 807 94


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