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)

Differently from target-based anticancer drugs, molecular mechanisms of actions are not well-known in many of the classical antineoplastic agents. With the exception of vinca alkaloids and taxanes, all of the classical antineoplastic agents work on DNA metabolism in cells and can therefore be categorised as 'DNA metabolism inhibitor'. Cellular sensitivity against these drugs largely depends on various activities in DNA metabolism, particularly in DNA repair. However, DNA repair as a determinant of drug sensitivity had long received little attention. DNA mismatch repair (MMR) is now regarded as an important determinant to alter cellular sensitivities against various drugs including fluoropyrimidines, platinum compounds and topoisomerase inhibitors. However, molecular mechanisms of this connection are still unknown. In particular, the relationship between MMR and 5-fluorouraci (l 5-FU) sensitivity is now being approached by examining the tumour MMR status and clinical outcomes in colorectal cancer patients treated with 5-FU-based adjuvant chemotherapies. However, reported results lack consistency, possibly due to the methodological problems in assays used to determine the MMR status. On the other hand, nucleotide excision repair (NER) is also regarded as an important determinant of cisplatin (CDDP) sensitivity. Expression of ERCC 1, a component of this complex multi-protein system, has been reported to be a determinant of prognosis in CDDP-treated non-small-cell lung cancer patients. In order to establish the significance of DNA repair as a determinant of tumour chemosensitivity, further basic studies, particularly ones approached from biochemical viewpoints, are required. Clinical studies supported by accurate assay techniques are also needed.
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PMID:[DNA repair as a determinant of tumour chemosensitivity]. 1735 24

Amrubicin is a totally synthetic anthracycline anticancer drug and a potent topoisomerase II inhibitor. Recently, amrubicin was approved in Japan for the treatment of small- and non-small-cell lung cancers (SCLC and NSCLC). Here, we review the efficacy and toxicities of amrubicin monotherapy and amrubicin in combination with cisplatin for extensive-disease SCLC (ED-SCLC), and of amrubicin monotherapy for advanced NSCLC, as observed in the clinical trials. Recommended dosage for previously untreated advanced NCSLC was 45 mg/m2/day by intravenous administration for 3 days. Dose-limiting toxicities were leucopenia, thrombocytopenia, and gastrointestinal disturbance. Response rate was 27.9% for advanced NSCLC, and 75.8% for ED-SCLC with a median survival time (MST) of 11.7 months. Recommended dosage of amrubicin was 40 mg/m2/day in combination with cisplatin at 60 mg/m2/day, with MST of 13.6 months and 1-year survival rate of 56.1%. In sensitive or refractory relapsed SCLC, response rate was 52 and 50%, progression-free survival was 4.2 and 2.6 months, overall survival was 11.6 and 10.3 months, and 1-year survival rate was 46 and 40%, respectively. These results are promising for the treatment of both NSCLC and SCLC. Further clinical trials will clarify the status of amrubicin in the treatment of lung cancer.
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PMID:Amrubicin for non-small-cell lung cancer and small-cell lung cancer. 1762 45

Nonsmall-cell lung cancer (NSCLC) is not generally a chemosensitive tumor, and the mechanism of resistance to the relevant anticancer drugs has not been fully elucidated. Solamargine (SM), the major steroidal glycoalkaloids extracted from the Chinese herb Solanum, inhibits the growth of human tumor cells. We have previously demonstrated that SM regulates tumor necrosis factor receptors (TNFRs)- and mitochondria-mediated pathways and sensitizes NSCLC cells to initiate apoptosis. Interestingly, this investigation reveals that SM up-regulated Fas expression and down-regulated the expression of HER2, whose overexpression is associated with resistance to drugs, and promotes chemotherapy-induced apoptosis in NSCLC A549 and H441 cells. After treatment with SM, the expression of HER2 mRNA was correlated with the expression of topoisomerase IIalpha (TOP2A) mRNA. The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death. Therefore, the downregulation of the HER2 and TOP2A expression by SM with epirubicin may partially explain the SM and epirubicin cytotoxicity synergy effect in NSCLC. Results of this study suggest that SM induces Fas and TNFR-induced NSCLC cell apoptosis and reduces HER2 expression. These findings provide the synergistic therapeutic interaction between SM and epirubicin, suggesting that such combinations may be effectively exploited in future human cancer clinical trials.
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PMID:Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells. 1763 97

We have previously demonstrated that solamargine (SM), the major steroidal glycoalkaloid extracted from Chinese herb Solanum plants, reveals down-regulation of HER2 and up-regulation of Fas and tumor necrosis factor receptor (TNFR) expressions, triggers the mitochondria-mediated cell apoptosis pathway, and sensitizes human nonsmall cell lung cancer (NSCLC) H441 and A549 adenocarcinoma cells to chemotherapy. The present study shows that SM enhances HER2 expression in NSCLC large cell carcinoma H661 and small cell lung cancer (SCLC) H69 cells and may increase the susceptibility of the cells to trastuzumab, the humanized anti-HER2 antibody. The combinational treatment of SM and trastuzumab synergistically augments and inhibits H661 and H69 cell proliferation. After treatment with SM, coexpression of HER2 and topoisomerase IIalpha (TOP2A) H661 and H69 cells is more sensitive to the TOP2 inhibitor, epirubicin. The combinatory use of low concentrations of SM with the low-toxic epirubicin accelerated greater apoptotic cell death than each drug did alone in H661 and H69 cells. Relevant studies have shown that HER2 overexpressing cancer cells are more resistant than HER2 low-expressing cells to the chemotherapeutic agent and tumor necrosis factor-induced apoptosis. These investigations have indicated that HER2 overexpression does not suffice to induce intrinsic and pleomorphic drug resistance. The data presented herein suggest that the expression of HER2 did not influence the SM-induced apoptosis of different types of lung cancer cells and that the SM up-regulation of HER2 and TOP2A expressions simultaneously augmented trastuzumab and epirubicin-induced deaths of lung cancer H661 and H69 cells.
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PMID:Solamargine enhances HER2 expression and increases the susceptibility of human lung cancer H661 and H69 cells to trastuzumab and epirubicin. 1807 28

Microchip-based systems have many desirable characteristics and can be used in much cellular biochemical analysis. Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone, has a critical role in chemotherapy resistance of some cancers. This work aimed at analyzing the correlation between the expression of GRP78 and an anticancer drug, topoisomerase II inhibitor-VP-16, in human lung cancer cell line NCI-H460 using this microchip-based system. The cells were cultured on a PDMS chip, the expression of GRP78 at both protein and mRNA levels for the cells under the condition with or without the induction of A23187 were assayed by immunofluorescence and chip electrophoresis, respectively. Then the cells were treated by VP-16, percentages of apoptosis and the cycle distributions of the cells were detected by flow cytometry. The cells cultured on the PDMS attached and spread well to micro-channels with high viability. Compared with the non-induced cells, the expression of GRP78 at both protein and mRNA levels for the A23187-induced cells were increased greatly. After treatment by VP-16, the percentage of apoptotic cells decreased nearly threefold for the A23187-induced cells in contrast to the non-induced cells (13.15 +/- 3.84% versus 34.03 +/- 11.45%), and the cells distributed in S phase reduced dramatically (11.96 +/- 1.27% versus 20.76 +/- 3.05%) whereas in G(1) phase increased greatly (74.16 +/- 0.95% versus 57.06 +/- 4%). GRP78 is correlated to the resistance to VP-16 in human lung cancer cell line. The microchip-based system has the potential application and feasibility for cell culture and its functional research.
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PMID:The analysis of chemotherapy resistance in human lung cancer cell line with microchip-based system. 1836 95

Ellipticine and its analogues were reported as topoisomerase II inhibitors and promising antitumor agents. In this work, we showed that the growth of human non-small-cell-lung-cancer (NSCLC) epithelial cells A549 can be inhibited by ellipticine. The inhibitory effect was reverted by PI3K inhibitors. The sub-G(1) phase cells after ellipticine treatment appeared at the expense of those that accumulated first at S- and G(2)/M phases during the early stage of treatment. We showed that the progression leading to cell death was impaired by wortmannin, which reverted apoptosis by retaining cells at S- and G(2)/M transition states. The characteristic apoptosis marker p53 activation after treatment appeared first followed by poly(ADP-ribose)polymerase (PARP) fragmentation. They disappeared upon co-treatment with wortmannin and the apoptotic phenotype reversed. Furthermore, ellipticine regulated endogenous survival signaling by up-regulating phosphorylated Akt that returned to its basal level later. Furthermore, ellipticine induced nucleus translocalization of p53 and Akt and recruitment of autophagosomes. The autophagic-related cell death was interfered by wortmannin and the suppressed growth reverted. The Akt-related cell death also occurred in p53-deficient cells with stable expression of exogenous p53. The work showed that ellipticine-induced cytotoxicity in NSCLC cells was achieved through autophagy and apoptotic death as a result of Akt-modulation. Being a topoisomerase II inhibitor, ellipticine proved a regulator in autophagy-related cell death through corporation of p53 and Akt.
Lung Cancer 2009 02
PMID:Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells. 2759 91

Asulacrine (ASL) is an inhibitor of topoisomerase II, which has shown potential against breast and lung cancer. It is a poorly water soluble drug. To allow intravenous (i.v.) administration, ASL was formulated as a nanocrystalline suspension by high pressure homogenization. The nanosuspension was lyophilized to obtain the dry ASL nanoparticles (average size, 133+/-20nm), which enhanced both the physical and chemical stability of the ASL nanoparticles. ASL dissolution and saturation solubility were enhanced by the nanosuspension. Differential scanning calorimetry and X-ray diffraction analysis showed that the crystallinity of the ASL was preserved during the high pressure homogenization process. The pharmacokinetics and tissue distribution of ASL administered either as a nanosuspension or as a solution were compared after i.v. administration to mice. In plasma, ASL nanosuspension exhibited a significantly (P<0.01) reduced C(max) (12.2+/-1.3microg ml(-1)vs 18.3+/-1.0microg ml(-1)) and AUC(0-infinity) (18.7+/-0.5microg ml(-1)h vs 46.4+/-2.6microg ml(-1)h), and a significantly (P<0.01) greater volume of distribution (15.5+/-0.6lkg(-1)vs 2.5+/-0.1lkg(-1)), clearance (1.6+/-0.04lh(-1)kg(-1)vs 0.6+/-0.04lh(-1)kg(-1)) and elimination half-life (6.1+/-0.1h vs 2.7+/-0.2h) compared to the ASL solution. In contrast, the ASL nanosuspension resulted in a significantly greater AUC(0-infinity) in liver, lung and kidney (all P<0.01), but not in heart.
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PMID:Formulation and pharmacokinetic evaluation of an asulacrine nanocrystalline suspension for intravenous delivery. 1884 73

Although the advancement of the chemotherapy of non-small cell lung cancer and small cell lung cancer is remarkable in recent years, it is still unsatisfactory. Therefore, some new agents or a new treatment strategy for lung cancer is required. Amrubicin is a totally synthetic anthracycline anticancer drug that acts as a potent topoisomerase II inhibitor. Recently, amrubicin has been approved in Japan for the treatment of small- and non-small cell lung cancers and some clinical trials about amrubicin were conducted in Japan, and promising results have been reported for the treatment of small cell lung cancer in particular. The preclinical, pharmacology and clinical data of amrubicin for the treatment of advanced lung cancer are reviewed.
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PMID:Amrubicin for the treatment of advanced lung cancer. 1923 96

Malignant pleural mesothelioma is an asbestos-related multi-resistant tumour with increasing incidence worldwide. Well-characterized snap-frozen normal parietal, visceral pleura and mesothelioma samples were analysed with Affymetrix Human Genome U133 Plus 2.0 GeneChip oligoarray of 38500 genes. We discovered a close relation between gene profile and resistance towards topoisomerase poisons, alkylating agents, antitubulines, antifolates, platinum compounds and radiation therapy. Target genes of chemo- (e.g. TOP2A, BIRC5/Survivin and proteasome) and radiotherapy (e.g. BRCA2, FANCA, FANCD2, CCNB1 and RAD50) were significantly overexpressed. The Fanconi anemia/BRCA2 pathway, responsible for homologous recombination DNA repair appears as a key pathway in both chemo- and radio-resistance of mesothelioma. Leukocyte trans-endothelial migration gene down-regulation could partly explain resistance against immunological therapies. Gene expression features found in other resistant cancer types related to DNA repair and replication are shared by mesothelioma and could represent general features of tumour resistance. Targeted suppression of some of those key genes and pathways combined with chemotherapy or radiation could improve the outcome of mesothelioma therapy. We propose CHEK1, RAD21, FANCD2 and RAN as new co-targets for mesothelioma treatment. The pro-angiogenic AGGF1 mRNA and protein was highly overexpressed in all tumours and may serve as a target for anti-angiogenic treatment. Overexpression of NQO1 may render mesothelioma sensitive to the novel compound beta-Lapachone.
Lung Cancer 2010 Jan
PMID:Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets. 1938 Jan 73

Current issues in cancer research involve searching for novel anticancer compounds that can be used to regulate the cell cycle and lead to more effective treatments of tumors. In this study, it was hypothesized that possessing a cyclic alkaloid similar to harmine, arborescidines can disrupt the proliferative state of cancer cells and block the activity of topoisomerases. The antiproliferative activity of arborescidines A-C and their derivatives was evaluated in vitro against four human tumor cell lines: gastric adenocarcinoma, lung cancer, bladder carcinoma and leukemia. Assuming the mechanism of action by topoisomerase II binding model, the compounds possessing the greatest activity had nonpolar side-chain into hydrophobic binding region on the DNA/topo II complex.
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PMID:Antiproliferative activity of arborescidine alkaloids and derivatives. 1941 3


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