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)

Small-cell lung cancer (SCLC) cells may express somatostatin receptors [14]. Receptor-positive tissue can be visualised in vivo by scintigraphy with radiolabelled somatostatin analogues. In a prospective study we examined 18 patients with histologically proven SCLC for the diagnostic value of somatostatin receptor scintigraphy using indium-111 pentetreotide. Planar whole body scanning was performed 4 and 24 hours after administration. Additional SPECT imaging of the thorax and the abdomen was done at 24 hours. The results were compared with conventional staging procedures: ultrasound, x-ray, computed tomography and bone scintigraphy. In all 18 patients the primary tumour was correctly identified. Out of 13 patients with mediastinal lymphoma formation 10 patients showed positive SRS. In 2 more patients SRS showed mediastinal uptake while CT scanning was negative. The detection of distant metastases in patients with extensive disease was true positive in 8 cases (OSS, HEP, BRA), false negative in 4 cases (PLE, ADR, HEP), corresponding to a sensitivity of 67%. In 2 patients cerebral metastases were no longer detectable by SRS after previous local irradiation. Even though the method is limited in respect of revealing distant metastases in the upper abdominal area due to physiological uptake in liver, spleen and kidneys, differentiation between limited disease (LD) and extensive disease (ED) was possible in all cases. We conclude that [111In]pentetreotide scintigraphy is a suitable method for the detection of SCLC primary tumours and a substantial tool for differentiation between LD and ED if combined with ultrasonography of the upper abdomen.
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PMID:[Diagnostic value of somatostatin receptor scintigraphy with indium-111 pentetreotide in small-cell bronchial carcinoma]. 955 59

Doxorubicin is cardiotoxic and its use must be monitored carefully. Incidence of refractory cardiac failure is shown to increase once the cumulative dose exceeds 450 mg/m2. However, significant decline of ejection fraction (EF) may occur even at lower dose levels. EF was monitored using Multigated Radionuclide Angiography (MUGA) scan of all consecutive lung cancer patients, treated with Doxorubicin based regimens. Thirteen of 82 patients showed a significant (more than 15%) decline of left ventricular EF. The dose of doxorubicin producing this decline ranged between 91-180 mg/m2. Actual decline in EF ranged between 16-45%. Only 5 of 13 patients developed symptoms attributable to the cardiac disease. Doxorubicin can alter EF significantly in lung cancer patients at levels well below which are considered 'safe'. The reason for massive decline in ejection fraction in these patients has been hypothesized.
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PMID:Doxorubicin cardiomyopathy in lung cancer patients. 981 76

The effect on cytotoxicity of combining a range of clinically important non-steroidal anti-inflammatory drugs (NSAIDs) with a variety of chemotherapeutic drugs was examined in the human lung cancer cell lines DLKP, A549, COR L23P and COR L23R and in a human leukaemia line HL60/ADR. A specific group of NSAIDs (indomethacin, sulindac, tolmetin, acemetacin, zomepirac and mefenamic acid) all at non-toxic levels, significantly increased the cytotoxicity of the anthracyclines (doxorubicin, daunorubicin and epirubicin), as well as teniposide, VP-16 and vincristine, but not the other vinca alkaloids vinblastine and vinorelbine. A substantial number of other anticancer drugs, including methotrexate, 5-fluorouracil, cytarabine, hydroxyurea, chlorambucil, cyclophosphamide, cisplatin, carboplatin, mitoxantrone, actinomycin D, bleomycin, paclitaxel and camptothecin, were also tested, but displayed no synergy in combination with the NSAIDs. The synergistic effect was concentration dependent. The effect appears to be independent of the cyclo-oxygenase inhibitory ability of the NSAIDs, as (i) the synergistic combination could not be reversed by the addition of prostaglandins D2 or E2; (ii) sulindac sulphone, a metabolite of sulindac that does not inhibit the cyclooxygenase enzyme, was positive in the combination assay: and (iii) many NSAIDs known to be cyclo-oxygenase inhibitors, e.g. meclofenamic acid, diclofenac, naproxen, fenoprofen, phenylbutazone, flufenamic acid, flurbiprofen, ibuprofen and ketoprofen, were inactive in the combination assay. The enhancement of cytotoxicity was observed in a range of drug sensitive tumour cell lines, but did not occur in P-170-overexpressing multidrug resistant cell lines. However, in the HL60/ADR and COR L23R cell lines, in which multidrug resistance is due to overexpression of the multidrug resistance-associated protein MRP, a significant increase in cytotoxicity was observed in the presence of the active NSAIDs. Subsequent Western blot analysis of the drug sensitive parental cell lines, DLKP and A549, revealed that they also expressed MRP and reverse-transcription-polymerase chain reaction studies demonstrated that mRNA for MRP was present in both cell lines. It was found that the positive NSAIDs were among the more potent inhibitors of [3H]-LTC4 transport into inside-out plasma membrane vesicles prepared from MRP-expressing cells, of doxorubicin efflux from preloaded cells and of glutathione-S-transferase activity. The NSAIDs did not enhance cellular sensitivity to radiation. The combination of specific NSAIDs with anticancer drugs reported here may have potential clinical applications, especially in the circumvention of MRP-mediated multidrug resistance.
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PMID:Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs). 984 88

The multidrug resistance-associated protein (MRP) is a drug efflux membrane pump conferring multidrug resistance on tumor cells. In order to look for compounds that can lead to reversal of such a resistance, the antituberculosis compound rifampicin, belonging to the chemical class of rifamycins, was examined for its effect on MRP activity in human multidrug resistant lung cancer GLC4/ADR cells. Rifampicin was shown to increase accumulation of the MRP substrate calcein in GLC4/ADR cells in a dose-dependent manner by inhibiting its MRP-mediated efflux from the cells; it also enhanced intracellular retention of another substrate of MRP such as the anticancer drug vincristine in the resistant cells. By contrast, the antituberculosis drug did not alter cellular levels of accumulation of either calcein or vincristine in parental drug-sensitive GLC4 cells. Other rifamycins such as rifamycin B and rifamycin SV were also demonstrated to increase intracellular accumulation of calcein in GLC4/ADR cells. These results therefore indicate that rifamycins, including rifampicin, probably constitute a new chemical class of modulators down-regulating MRP-mediated drug transport.
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PMID:Inhibition of multidrug resistance-associated protein (MRP) activity by rifampicin in human multidrug-resistant lung tumor cells. 1040 15

Coupling anticancer drugs to synthetic polymers is a promising approach of enhancing the antitumor efficacy and reducing the side-effects of these agents. Doxorubicin maleimide derivatives containing an amide or acid-sensitive hydrazone linker were therefore coupled to alpha-methoxy-poly(ethylene glycol)-thiopropionic acid amide (MW 20000 Da), alpha,omega-bis-thiopropionic acid amide poly(ethylene glycol) (MW 20000 Da) or alpha-tert-butoxy-poly(ethylene glycol)-thiopropionic acid amide (MW 70000 Da) and the resulting polyethylene glycol (PEG) conjugates isolated through size-exclusion chromatography. The polymer drug derivatives were designed as to release doxorubicin inside the tumor cell by acid-cleavage of the hydrazone bond after uptake of the conjugate by endocytosis. The acid-sensitive PEG conjugates containing the carboxylic hydrazone bonds exhibited in vitro activity against human BXF T24 bladder carcinoma and LXFL 529L lung cancer cells with IC70 values in the range 0.02-1.5 microm (cell culture assay: propidium iodide fluorescence or colony forming assay). In contrast, PEG doxorubicin conjugates containing an amide bond between the drug and the polymer showed no in vitro activity. Fluorescence microscopy studies in LXFL 529 lung cancer cells revealed that free doxorubicin accumulates in the cell nucleus whereas doxorubicin of the acid-sensitive PEG doxorubicin conjugates is primarily localized in the cytoplasm. Nevertheless, the acid-sensitive PEG doxorubicin conjugates retain their ability to bind to calf thymus DNA as shown by fluorescence and visible spectroscopy studies. Results regarding the effect of an acid-sensitive PEG conjugate of molecular weight 20000 in the chorioallantoic membrane (CAM) assay indicate that this conjugate is significantly less embryotoxic than free doxorubicin although antiangiogenic effects were not observed.
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PMID:Acid-sensitive polyethylene glycol conjugates of doxorubicin: preparation, in vitro efficacy and intracellular distribution. 1063 61

Anticancer drugs exert at least part of their cytotoxic effect by triggering apoptosis. We previously identified chemotherapy-induced apoptosis in lung cancer cells and suggested a role for p53 alternative or complementary pathways in this process. Recently, a role for the Fas/FasL (CD95/Apo1) signaling system in chemotherapy-induced apoptosis was proposed in some cell types. In the present work, the involvement of the Fas/FasL system in drug-induced apoptosis in lung cancer cells was investigated upon exposure to four cytotoxic drugs (cisplatin, gemcitabine, topotecan, and paclitaxel). We assessed the expression of Fas and FasL and the function of the Fas pathway in six lung cancer cell lines (H460, H322, GLC4, GLC4/ADR, H187, and N417). All lung cancer cell lines expressed Fas and FasL at RNA and protein levels, and apoptosis could be induced in four of six cell lines upon exposure to the Fas agonistic monoclonal antibody (mAb) CLB-CD95/15. Nevertheless, after drug exposure, no significant FasL up-regulation was observed, whereas the Fas expression was increased in the wild-type p53 cell line H460, but not in the other lines, proved to be mutant p53 by direct gene sequencing. Moreover, no correlation was observed in lung cancer cell lines between sensitivity to drugs and to a Fas agonistic mAb, and preincubation of cells with either the Fas-antagonistic mAb CLB-CD95/2 or a FasL-neutralizing mAb did not protect from drug-induced apoptosis. Taken together, these observations strongly argue against a role of the Fas/FasL signaling pathway in drug-induced apoptosis in lung cancer cells. Interestingly, caspase-8 activation was observed upon drug exposure, independently from Fas/FasL signaling.
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PMID:Drug-induced apoptosis in lung cnacer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway. 1065 51

Doxorubicin is the most widely studied agent for the treatment of malignant mesothelioma. In conventional doses, the response rate is approximately 17%. Higher dose doxorubicin has been successfully employed in other tumor types. Dexrazoxane has been demonstrated to reduce the cardiac toxicity associated with long term, chronic use of doxorubicin. Based upon phase I data generated by the Cancer and Leukemia Group B (CALGB) indicating that doxorubicin at a dose of 120 mg/m(2) when combined with dexrazoxane and GM-CSF could be safely administered, the CALGB undertook a phase II study of high-dose doxorubicin in patients with malignant mesothelioma. Toxicity was excessive, necessitating protocol modification and ultimately protocol termination. There were no objective responses observed. We conclude that high-dose doxorubicin administered with dexrazoxane is unacceptably toxic in this patient population.
Lung Cancer 2001 Nov
PMID:High-dose doxorubicin, dexrazoxane, and GM-CSF in malignant mesothelioma: a phase II study-Cancer and Leukemia Group B 9631. 1167 88

The rat monoclonal antibody LMR-42 has previously been shown to react with an external epitope of a plasma membrane protein with a M(r) of approximately 55,000 that was upregulated in multidrug-resistant (MDR) tumour cells. Here, we report the isolation of the cDNA encoding the LMR-42 antigen from the MDR human fibrosarcoma cell line HT1080/DR4 and the lung cancer cell line GLC4/ADR by expression cloning. Sequence analysis showed that the LMR-42 antigen is identical to the endothelial cell protein C receptor (EPCR). Using the LMR-42 Mab for cytochemical analyses of a disease-oriented panel of 45 non-drug selected tumour cell lines of the National Cancer Institute (NCI), we found high EPCR expression in 47% of the primary tumour cell lines, including melanomas, renal- and colon carcinomas. In a small panel of human tumours, occasionally very high EPCR expression was detected in endothelial vessels, but expression in the tumour cells was a rare event. The functional significance of overexpression of EPCR on both primary and drug-selected tumour cells is still unclear. As the protein is related to MHC class I molecules and shares no characteristics with any of the currently known transporter proteins, EPCR is not expected to play a causal role in the resistant phenotype of the MDR tumour cells. Nevertheless, exposure of tumour cells to cytostatic drugs may frequently lead to EPCR overexpression. Since EPCR is known to play a pivotal role in preventing blood coagulation through binding of (activated) protein C, it might endow tumour cells, both of mesenchymal and epithelial derivations, with increased growth potential by local anti-coagulant activity.
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PMID:Expression of the vascular endothelial cell protein C receptor in epithelial tumour cells. 1211 May 1

Resistance to chemotherapeutic agents is the major reason for treatment failure of cancer chemotherapy. Some chemotherapeutic drugs induce the activation of NF-kappaB in cancer cells that results in their resistance to anticancer drugs. But the role of NF-kappaB in acquired resistance has not been well investigated. In this study, we transferred the "super-repressor" form of the NF-kappaB inhibitor by adenoviral vector (ad-IkappaBalpha) to human lung cancer cell lines with resistant to cisplatin (PC-14-DDP) and adriamycin (PC-14-ADR), and observed the sensitivity change. Electrophoretic mobility shift assay showed that ad-IkappaBalpha blocked the activation of NF-kappaB induced by cisplatin and adriamycin. Transduction with ad-IkappaBalpha restored the sensitivity of cisplatin and adriamycin resistant lung cancer cell lines (PC-14-DDP and PC-14-ADR) to a level compatible to the parental cell lines. Annexin-V analysis suggested that the enhancement of chemosensitivity was probably a result of the induction of apoptosis. These data demonstrated that ad-IkappaBalpha blockade of chemotherapeutic induced NF-kappaB activation increased apoptosis induction and the chemosensitivity of lung cancer cell lines with acquired resistance to cisplatin and adriamycin. Therefore, gene transfer of IkappaBalpha-SR seems to represent a new therapeutic strategy for the solution of low sensitivity and lung cancer resistance to anticancer drugs.
Lung Cancer 2003 Aug
PMID:The effect of adenovirus-IkappaBalpha transduction on the chemosensitivity of lung cancer cell line with resistance to cis-diamminedichloroplatinum(II)(cisplatin) and doxorubicin(adriamycin). 1287 83

In the present study, we describe the cytotoxicity of the new drug prodigiosin (PG) in two small cell lung carcinoma (SCLC) cell lines, GLC4 and its derived doxorubicin-resistant GLC4/ADR cell line, which overexpresses multidrug-related protein 1 (MRP-1). We observed through Western blot that PG mediated cytochrome c release, caspase cascade activation and PARP cleavage, thereby leading to apoptosis in a dose-response manner. MRP-1 expression increased after PG treatment, although that does not lead to protein accumulation. The MTT assay showed no difference in sensitivity to PG between the two cell lines. Our results support PG as a potential drug for the treatment of lung cancer as it overcomes the multidrug resistance phenotype produced by MRP-1 overexpression.
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PMID:High cytotoxic sensitivity of the human small cell lung doxorubicin-resistant carcinoma (GLC4/ADR) cell line to prodigiosin through apoptosis activation. 1574 75


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