Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanisms contributing to reduced cytotoxic drug accumulation were studied in two multidrug-resistant (MDR) human lung cancer cell lines without P-glycoprotein expression. In these (non-small cell) SW-1573/2R120 and (small cell) GLC4/ADR MDR cells, the steady-state accumulation of [14C]daunorubicin was 30 and 12%, respectively, of that in the parent cells. When cells, at steady state, were permeabilized with digitonin, the amount of daunorubicin binding increased only in the resistant cells. The reduced accumulation of daunorubicin in the SW-1573/2R120 and GLC4/ADR cells was accompanied by a lower initial (2 min) uptake rate of this drug. No difference in initial efflux rate of daunorubicin from preloaded cells could be detected between sensitive and resistant SW-1573 cells. However, daunorubicin was extruded 5-fold faster from GLC4/ADR cells than from the parental cells. In the presence of the energy metabolism inhibitors sodium azide and deoxyglucose, the reduced daunorubicin accumulations in the SW-1573/2R120 and GLC4/ADR MDR cells were (almost) completely reversed. The effects of these inhibitors on drug uptake were already apparent during the earliest measured time points (less than 15 s). Also, the enhanced efflux of daunorubicin from GLC4/ADR cells was inhibited. In ATP-depleted cells, the intracellular pH was lowered by approximately 0.3 units in resistant as well as in sensitive cells. The lower intracellular pH, however, could not account for the increase in daunorubicin accumulation in the resistant cells. Also, for vincristine and etoposide, the increases in drug accumulation under energy-deprived conditions were more pronounced in the resistant SW-1573/2R120 cells than in the parent SW-1573 cells. These results suggest that accumulation of drugs in the non-P-glycoprotein MDR human lung carcinoma cell lines SW-1573/2R120 and GLC4/ADR is reduced by an energy-dependent drug export mechanism which prevents efficient transport of drug to the target. Since P-glycoprotein expression in lung tumors is generally low, these MDR lung cancer cell lines can be used as a model to study alternative mechanisms leading to multidrug resistance in this tumor type.
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PMID:Energy-dependent processes involved in reduced drug accumulation in multidrug-resistant human lung cancer cell lines without P-glycoprotein expression. 130 22

Human lung cancer transplanted into athymic mice contains predominantly an acidic variant (designated B1) of lysosomal arylsulfatase B. B1 enzyme was suggested to be phosphorylated and sialylated (Gasa, S., Makita, A., Kameya, T., Kodama, T., Koide, T., Tsumuraya, M., and Komai, T. (1981) Eur. J. Biochem. 116, 497-503). In order to determine the localization of phosphate in B1 enzyme, we labeled in vivo the transplanted tumor with [32P]H3PO4 or [3H]glucosamine and purified B1 enzyme by immunoprecipitation. Bio-Gel chromatography of the labeled B1 enzyme treated with endoglycosidase H demonstrated that both the excluded and included materials were labeled with 32P and 3H. From acid hydrolysate of the excluded materials, phosphorylated serine and threonine were detected. Protein phosphorylation of arylsulfatase was confirmed by in vitro labeling experiments with [gamma-32P]ATP. By incubation of the tumor homogenate with ATP followed by isolation of the enzymes, B1 enzyme had a significant amount of radioactivity, whereas the B enzyme had little; by exogenous protein kinase, partially purified B enzyme was phosphorylated 35 times more than B1 enzyme. Acid hydrolysate of the included materials in the Bio-Gel column demonstrated mannose 6-phosphate and an unknown phosphorylated compound which migrates more than Man-6-P on electrophoresis and chromatography.
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PMID:Phosphorylation on protein and carbohydrate moieties of a lysosomal arylsulfatase B variant in human lung cancer transplanted into athymic mice. 640 42

The ATP-dependent glutathione S-conjugate export pump (GS-X pump) has been suggested to play a role in the mechanism of cisplatin resistance. The purpose of this study was to determine the relationship between intracellular glutathione (GSH) levels and GS-X pump activity and whether GS-X pump overexpression results in cisplatin resistance. We transfected the human gamma-glutamylcysteine synthetase (gamma-GCS) gene into a human small-cell lung cancer cell line, SBC-3, producing SBC-3/GCS. The intracellular GSH content of SBC-3/GCS was twice that of the parental line, its GS-X pump activity was significantly enhanced and cellular cisplatin accumulation decreased. SBC-3/GCS showed higher resistance (relative resistance value of 7.4) to cisplatin than the parental line SBC-3. These data indicate that gamma-GCS gene overexpression induces cellular cisplatin resistance associated with increases in both the GSH content and GS-X pump activity, resulting in reduced cisplatin accumulation. In conclusion, GS-X pump expression is related to cellular GSH metabolism and involved in cisplatin resistance.
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PMID:Gamma-glutamylcysteine synthetase gene overexpression results in increased activity of the ATP-dependent glutathione S-conjugate export pump and cisplatin resistance. 748 97

In this study the ability of five novel anti-oestrogens [4-iodotamoxifen, pyrrolidino-4-iodotamoxifen, ethyl bromide tamoxifen (EBTx), ICI 164,384 (ICI 164) and ICI 182,780] to alter drug toxicity to multidrug resistant cell lines have been compared. The effect of these compounds on ATP-dependent vinblastine (VBL) transport was also tested using inside-out vesicles (IOV) prepared from highly P-glycoprotein (Pgp)-expressing CCRF-CEM/VBL1000 cells. The pure anti-oestrogen ICI 164 was most effective, enhancing doxorubicin and VBL toxicity to MCF-7Adr cells 25- and 35-fold, respectively, and was also the best inhibitor of ATP-dependent [3H]VBL accumulation by IOV. Pure anti-oestrogens, tamoxifen and iodotamoxifens completely reversed VBL resistance in the mdr1 transfected lung cancer cell line, S1/1.1, where resistance relative to wild-type cells was mediated solely by Pgp. The membrane impermeant tamoxifen derivative EBTx did not modify drug resistance, yet was as effective an inhibitor of VBL accumulation by inside-out Pgp-positive vesicles as tamoxifen. This indicates an intracellular role for tamoxifen and its derivatives in the modulation of Pgp-mediated drug resistance.
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PMID:Reversal of P-glycoprotein-mediated multidrug resistance by pure anti-oestrogens and novel tamoxifen derivatives. 791 4

The 190-kDa multidrug resistance protein (MRP) has recently been associated with the transport of cysteinyl leukotrienes and several glutathione (GSH) S-conjugates. In the present study, we have examined the transport of leukotriene C4 (LTC4) in membrane vesicles from MRP-transfected HeLa cells (T14), as well as drug-selected H69AR lung cancer cells which express high levels of MRP. V(max) and K(m) values for LTC4 transport by membrane vesicles from T14 cells were 529 +/- 176 pmol mg(-1) min(-1) and 105 +/- 31 nM, respectively. At 50 nM LTC4, the K(m) (ATP) was 70 micron. Transport in T14 vesicles was osmotically-sensitive and was supported by various nucleoside triphosphates but not by non- or slowly-hydrolyzable ATP analogs. LTC4 transport rates in membrane vesicles derived from H69AR cells and their parental and revertant variants were consistent with their relative levels of MRP expression. A 190-kDa protein in T14 membrane vesicles was photolabeled by [3H]LTC4 and immunoprecipitation with MRP-specific monoclonal antibodies (mAbs) confirmed that this protein was MRP. LTC4 transport was inhibited by an MRP-specific mAb (QCRL-3) directed against an intracellular conformational epitope of MRP, but not by a mAb (QCRL-1) which recognizes a linear epitope. Photolabeling with [3H]LTC4 was also inhibitable by mAb QCRL-3 but not mAb QCRL-1. GSH did not inhibit LTC4 transport. However, the ability of alkylated GSH derivatives to inhibit transport increased markedly with the length of the alkyl group. S-Decylglutathione was a potent competitive inhibitor of [3H]LTC4 transport (K(i(app)) 116 nM), suggesting that the two compounds bind to the same, or closely related, site(s) on MRP. Chemotherapeutic agents including colchicine, doxorubicin, and daunorubicin were poor inhibitors of [3H]LTC4 transport. Taxol, VP-16, vincristine, and vinblastine were also poor inhibitors of LTC4 transport but inhibition by these compounds was enhanced by GSH. Uptake of [3H]vincristine into T14 membrane vesicles in the absence of GSH was low and not dependent on ATP. However, in the presence of GSH, ATP-dependent vincristine transport was observed. Levels of transport increased with concentrations of GSH up to 5 mM. The identification of an MRP-specific mAb that inhibits LTC4 transport and prevents photolabeling of MRP by LTC4, provides conclusive evidence of the ability of MRP to transport cysteinyl leukotrienes. Our studies also demonstrate that MRP is capable of mediating ATP-dependent transport of vincristine and that transport is GSH-dependent.
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PMID:Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. Demonstration of glutathione-dependent vincristine transport. 862 43

Overexpression of the human gamma-glutamylcysteine (gamma-GCS) gene resulted in cisplatin resistance with an increased glutathione (GSH) content, increased ATP-dependent glutathione S-conjugate export pump (GS-X pump) activity and decreased platinum accumulation in human lung cancer cells transfected with a gamma-GCS cDNA expression vector, as we previously reported. In this study, we examined the effects of buthionine sulfoximine (BSO), a specific inhibitor of gamma-GCS, to determine whether GSH depletion alters cisplatin resistance in a gamma-GCS-transfected cell line, SBC-3/GCS. In the presence of 10 microM BSO for 4 days, SBC-3/GCS still showed resistance to cisplatin, although it was partially reversed. Under these conditions, GS-X pump activity remained up-regulated in spite of low GSH content, and the platinum content was decreased. These data suggest that the GS-X pump itself influences cisplatin resistance, as well as cellular GSH content.
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PMID:Effect of glutathione depletion on cisplatin resistance in cancer cells transfected with the gamma-glutamylcysteine synthetase gene. 911 37

Serological analysis of a recombinant lung cancer cDNA expression library with the autologous patient serum led to the isolation of 20 clones representing 12 different genes: 4 of these were known genes, and the other 8 were previously unknown genes. Of the four known genes, aldolase A (NY-LU-1), previously shown to be overexpressed in lung cancer, was most frequently isolated. The other three genes were annexin XI, human HIV Rev-interacting protein Rip-1, and the human homologue of the ATP-binding arsA component of the bacterial arsenite transporter, all of which are known to be widely expressed in human tissues. Among the eight unknown genes, of most interest was NY-LU-12. Cloning of full-length NY-LU-12 showed that this cDNA was derived from the same gene as g16, a partially sequenced gene that mapped to the lung cancer tumor suppressor gene locus on chromosome 3p21. The reported g16 sequence, however, was significantly shorter (2433 versus 3591 bp). As a result of alternate splicing and subsequent frameshift, the reported g16 protein is 603 amino acids shorter than the NY-LU-12 product (1123 residues) at its COOH terminus and would therefore lack the epitopes recognized by the autologous serum. Analysis of the putative NY-LU-12 protein sequence predicted that it is a nuclear zinc finger protein with two RNA-binding domains, and Southern analysis showed that this gene is partially deleted in the lung cancer line NCI-H740 but not in nine other lung cancer lines. Screening of normal and cancer patient sera showed anti-NY-LU-12 seroreactivity in 2 of 21 allogeneic lung cancer patients but not in 24 patients with other tumors or in 16 sera from healthy donors. Comparison of NY-LU-12 cDNA from Lu15 tumor and normal lung tissue by DNA sequencing and/or single-strand conformation polymorphism analysis showed no evidence of mutation. Considering the high frequency of 3p21 alterations in lung cancer and the fact that the tumor suppressor gene or genes in this locus have not been identified, additional studies on the NY-LU-12 gene and its product are warranted.
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PMID:Human lung cancer antigens recognized by autologous antibodies: definition of a novel cDNA derived from the tumor suppressor gene locus on chromosome 3p21.3. 950 Apr 67

The most well-characterized mechanism of multidrug resistance (MDR) involves P-glycoprotein (Pgp), a transmembrane protein acting as an ATP-dependent drug efflux pump. The recognition of 99mTc-Sestamibi and other lipophilic cations as transport substrates for Pgp provided the necessary tool for the clinical assessment of Pgp function in patients with cancer. Many clinical studies from different institutions and trials including a variety of malignancies indicate that both tumor uptake and clearance of 99mTc-Sestamibi are correlated with Pgp expression and may be used for the phenotypic assessment of multidrug resistance. Although both parameters may predict tumor response to chemotherapy, the extraction of efflux rate constants appeared to provide a more direct index of Pgp function as compared to tracer uptake ratio allowing to trace a continuous spectrum of drug transport activity. Preliminary studies reported the use of MDR imaging agents to monitor the modulating ability of revertant compounds. Although the results support the feasibility of this approach, the alteration of tracer pharmacokinetics induced by the modulators certainly constitutes a challenge in the development of a simple functional test suitable in clinical practice. The extension of the acquired imaging methodology to tumors with redundant intrinsic resistant mechanisms such as lung cancer requires further investigations on the relative contribution and clinical relevance of each mechanism. Due to the multifactorial nature of the phenomenon, the development of new tracers with substrate specificity for other known drug transporters would hopefully help to dissect the complex array of cellular mechanisms contributing to treatment failure.
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PMID:Clinical imaging of multidrug resistance in cancer. 1042 7

Adenosine 5'-triphosphate (ATP) is a purine nucleotide found in every cell of the human body. In addition to its well established role in cellular metabolism, extracellular ATP and its breakdown product adenosine, exert pronounced effects in a variety of biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation and liver glycogen metabolism. These effects are mediated by both P1 and P2 receptors. A cascade of ectonucleotidases plays a role in the effective regulation of these processes and may also have a protective function by keeping extracellular ATP and adenosine levels within physiological limits. In recent years several clinical applications of ATP and adenosine have been reported. In anaesthesia, low dose adenosine reduced neuropathic pain, hyperalgesia and ischaemic pain to a similar degree as morphine or ketamine. Postoperative opioid use was reduced. During surgery, ATP and adenosine have been used to induce hypotension. In patients with haemorrhagic shock, increased survival was observed after ATP treatment. In cardiology, ATP has been shown to be a well tolerated and effective pulmonary vasodilator in patients with pulmonary hypertension. Bolus injections of ATP and adenosine are useful in the diagnosis and treatment of paroxysmal supraventricular tachycardias. Adenosine also allowed highly accurate diagnosis of coronary artery disease. In pulmonology, nucleotides in combination with a sodium channel blocker improved mucociliary clearance from the airways to near normal in patients with cystic fibrosis. In oncology, there are indications that ATP may inhibit weight loss and tumour growth in patients with advanced lung cancer. There are also indications of potentiating effects of cytostatics and protective effects against radiation tissue damage. Further controlled clinical trials are warranted to determine the full beneficial potential of ATP, adenosine and uridine 5'-triphosphate.
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PMID:Adenosine triphosphate: established and potential clinical applications. 1047 17

A pilot study on squamous cell lung carcinoma (LC) chemosensitivity in adenosine triphosphate cell viability chemosensitivity assay (ATP-CVA) was performed. Besides the histological investigation, a modified ATP-CVA was used for the analysis of cancer cell chemosensitivity to four drug regimens, including topotecan, a promising agent for non-small-cell lung cancer (NSCLC) chemotherapy. Results of in vitro chemosensitivity testing showed chemoresistance or only weak response in the predominant amount of tumors.
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PMID:Lack of squamous cell lung carcinoma in vitro chemosensitivity to various drug regimens in the adenosine triphosphate cell viability chemosensitivity assay. 1054 31


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