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)

Howiinol A (GHM-10) is a kind of phenylethylene pyrone compounds isolated from Goniothalamus howii. By using the techniques of cell growth curve determination, MTT test, soft agar colony assay and experimental therapy of transplantable tumors in mice, it is found that GHM-10 exerts potent inhibitory effect on cancer cells but its influence on normal cells is relatively slight; the sensitivity of a drug-resistant cell line, KB/VCR 2000, to GHM-10 is similar to its parent cell line KB. Remarkable therapeutic effect can be seen in mice bearing H22 hepatoma and Lewis lung cancer and in mice with ascetic sarcoma 180 when GHM-10 is orally or intraperitoneally administered. The IC50s of L1210 cells treated with GHM-10 for 1 and 24 h are 6.85 and 3.32 micrograms.ml-1 respectively. The ratio of IC50 1 h and IC50 24 h is only 2.06, indicating that the action of GHM-10 is conformed to a cell cycle non-specific cytotoxic agent. By using trypan blue exclusive test and morphological examination, it is demonstrated that the main effect of GHM-10 is to inhibit the cell proliferation. Flow cytometery technique is used to analyze the cell cycle of L1210 cells. The results show that to some extent, GHM-10 blocks the cell cycle transition from G1 phase to S phase. By using [3H] labeled precursor incorporation technique, it is shown that GHM-10 significantly suppresses the biosynthesis of DNA, RNA and protein in L1210 cells, and the DNA synthesis is mostly affected. At 1 h after the cells were treated with GHM-10, these inhibitory effects have already been irreversible, suggesting that GHM-10 may cause structural damage on DNA molecules. However, GHM-10 is unable to intercalate into DNA molecules or to destroy its structure directly. By using single cell gel electrophoresis and alkaline elution technology, it is confirmed that GHM-10 causes DNA molecule damage and single strand breakage in L1210 cells. Further studies show that GHM-10 markedly inhibits DNA dehelix induced by DNA topoisomerase II both inside and outside the cells, indicating that GHM-10 is acting as an inhibitor of DNA topoisomerase II.
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PMID:Anticancer effect of Howiinol A and its mechanism of action. 1126 Dec 1

Resistance to chemotherapy is common in non-small cell lung cancer. The aim of this study was to investigate the prognostic impact of in vitro established drug resistance markers on the response to chemotherapy in patients with advanced non-small cell lung cancer. Samples of 38 patients were analyzed by immunohistochemical staining, for topoisomerase IIalpha and IIbeta, Ki-67, MRP and LRP. In addition, mutation analysis of the topoisomerase IIalpha gene, the B/DNBS and the Tyr804 region, was performed. Lung tumor biopsies were taken prior for treatment with one of the following regimens; cisplatin/paclitaxel, cisplatin/VM26 or VP16, or carboplatin/VP16/ifosfamide. Seventeen patients obtained a partial response, 12 had stable disease and nine patients had progressive disease. None of the investigated markers was related with overall response rate. In one sample a point mutation in the B/DNBS region of the topo IIalpha gene was detected which substitutes IIe(510) with Val. This tumor had a partial response to four courses of cisplatin/VP16 treatment. The survival analysis showed that the patients with high topo IIalpha expressing tumors had a significantly worse survival compared with the patients with low or intermediate topo IIalpha expressing tumors. In conclusion, no relation was observed between expression of topoisomerase IIalpha, IIbeta, Ki-67, MRP or LRP and response rate. Furthermore, worse survival was seen in patients with high topoisomerase IIalpha expressing tumors. In one tumor sample, a newly described mutation in the B/DNBS region of the topo IIalpha gene was detected, which does not appear to be related to drug resistance.
Lung Cancer 2001 May
PMID:Topoisomerase IIalpha and other drug resistance markers in advanced non-small cell lung cancer. 1132 82

The candidate tumour suppressor gene, LUCA-15, maps to the lung cancer tumour suppressor locus 3p21.3. Overexpression of an alternative RNA splice variant of LUCA-15 has been shown to retard human Jurkat T cell proliferation and to accelerate CD95-mediated apoptosis. An antisense cDNA to the 3'-UTR of this splice variant was able to suppress CD95-mediated apoptosis. Here, we report that overexpression of LUCA-15 itself suppresses CD95-mediated apoptosis in Jurkat cells. This suppression occurs prior to the final execution stage of the CD95 signalling pathway, and is associated with up-regulation of the apoptosis inhibitory protein Bcl-2. LUCA-15 overexpression is also able to inhibit apoptosis induced by the protein kinase inhibitor staurosporine, but is not able to significantly suppress apoptosis mediated by the topoisomerase II inhibitor etoposide. These findings suggest that LUCA-15 is a selective inhibitor of cell death, and confirm the importance of the LUCA-15 genetic locus in the control of apoptosis.
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PMID:LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells. 1142 Jun 83

Inhibition of topoisomerase I by topotecan results in a compensatory increase in topoisomerase II levels associated with increased in vitro sensitivity of tumors to etoposide. Maximum synergy has been observed for the sequence of topotecan followed by etoposide. This is the pharmacologic rationale for the sequence of topotecan 0.4 mg/m(2) per day for 7 days continuous i.v. infusion, carboplatin i.v. on day 8, and etoposide 50 mg per day p.o. days 9 through 20. The carboplatin dosage was escalated from an AUC of 4 to 5 to 6 (Calvert formula). Up to six treatment cycles were administered at 28-day intervals. Eligible patients had metastatic non-small cell lung cancer (NSCLC) or extensive disease small lung cell lung cancer (SCLC), no prior chemotherapy, performance status 0-2, and adequate organ function. Follow-up was twice weekly in the first cycle for CBC and for topotecan and etoposide concentrations. Follow-up, thereafter, was weekly. Tumor response was assessed after two and six cycles and then as clinically indicated. At carboplatin AUCs of 4 and 5, no NCI grade 4 toxicity was observed in cycle 1 in cohorts of three patients each. At the AUC of 5, two patients experienced dose-limiting events after cycle 3, one grade 4 neutropenia lasting >3 days (no fever) and one failure to recover an absolute neutrophil count >1500/microl by day 35. This was, therefore, deemed the maximal tolerable dose. Number of treatment cycles per patient ranged between 1 and 6, and three patients completed six cycles. All patients were male, age 47-71, with NSCLC in one and SCLC in six. The patient with NSCLC had progressive disease after one cycle. One complete and three partial responses were observed in five patients with SCLC. Mean steady-state plasma concentrations during topotecan infusion ranged from 0.73 to 1.69 ng/ml, and mean etoposide concentrations ranged from 60 to 230 ng/ml. This sequence of topotecan, carboplatin, and etoposide appeared tolerable and active. Neutropenia was the dose-limiting toxicity.
Lung Cancer
PMID:Phase I and pharmacologic study of sequential topotecan, carboplatin, and etoposide. 1155 19

Topoisomerase targeting chemotherapy is an excellent strategy for lung cancer treatment. We studied the cytotoxic effects of exposure to topoisomerase I inhibitor SN-38 and topoisomerase II inhibitor etoposide (VP-16) in lung cancer cell line Ma-1 using WST-1 assay and isobologram analysis. Cells were concurrently or sequentially exposed to drugs for 30 minutes, 2 hours and 24 hours. Simultaneous exposure for 30 minutes showed antagonistic. However, 2 hours or 24 hours exposure resulted in additive or supra-additive interaction, respectively. Sequential exposures to SN-38 followed by VP-16 resulted in synergistic interaction for all schedules. Whereas, VP-16 followed by SN-38 resulted in sub-additive interaction for 30 minutes and 2 hours exposures, however, 24 hours exposure resulted in additive interaction. These findings suggest that maximum cytotoxic effects can be obtained when SN-38 precedes VP-16, and that prolonged simultaneous administration may circumvent antagonistic interaction between them. These findings may be useful in clinical trials.
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PMID:In vitro schedule dependency in the treatment of topoisomerase I and II inhibitor. 1155 90

Y box-binding protein-1 (YB-1), a member of the DNA binding protein family, interacts with inverted CCAAT boxes (Y-boxes). Y-boxes are located on the promoter of numerous genes, such as DNA topoisomerase IIalpha (Topo IIalpha), proliferating cell nuclear antigen (PCNA) and multidrug resistance 1 (MDR1). In this study, we used immunohistochemical (IHC) staining to detect YB-1 expression in 59 lung cancer tissues and to evaluate whether YB-1 expression was associated with the expression of YB-1 target genes such as Topo IIalpha, PCNA and MDR1 in human lung carcinoma. Twenty-eight out of 59 cases (47.5%) were stained positive for YB-1 in the cytoplasm, while 30 out of 59 cases (50.8%) were positive for PCNA in the nuclei. Topo IIalpha-positive cells were detected in 16 out of 59 cases (27.1%). Eight out of 59 cases (13.6%) had greater than 5% P-gp positive cells expression. There was a significant correlation between the YB-1 and Topo IIalpha expression in small cell lung cancer (SCLC) (p=0.0242). YB-1 expression also correlated with PCNA expression in non-small cell lung cancer (NSCLC) (p=0.0001). Higher levels of YB-1 expression were associated with T3-4 and Stage III-IV tumors in adenocarcinomas (p=0.0072; p=0.0168). In contrast, no relationship was found between YB-1 expression and P-gp expression. Our study suggests that YB-1 expression correlates with Topo IIalpha and PCNA expression in lung cancer.
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PMID:Expression of Y box-binding protein-1 correlates with DNA topoisomerase IIalpha and proliferating cell nuclear antigen expression in lung cancer. 1172 93

The efficacy of radiotherapy in locally advanced non-small-cell lung cancer is limited. One attempt to improve survival uses a combination of radiation and chemotherapy. These two modalities can be applied in sequence or concurrently, but results from phase III trials of combined therapy versus radiation alone have been inconsistent. Early studies were mostly negative, but more recent trials using platinum-based regimens have shown some survival benefit for combined treatments. The positive impact of chemotherapy has also been shown in a meta-analysis. In recent studies, concurrent chemotherapy and radiation appears better than sequential application. However, the benefit of the combined approach is modest and should be balanced against increased early and late toxicity. The role of new agents such as taxanes, vinorelbine, gemcitabine, and topoisomerase inhibitors in combined modality therapy of non-small-cell lung cancer warrants further clinical investigation.
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PMID:Combined chemotherapy and radiation in locally advanced non-small-cell lung cancer. 1190 49

Tumour recurrence following chemotherapy remains a major obstacle to the cure of many cancers. This is exemplified by small-cell lung cancer (SCLC). Host-tumour interactions are central to tumour survival and proliferation. We hypothesized that a factor(s) within the local environment of SCLC cells could provide a survival signal or block a death signal, thereby accounting for the protection of SCLC cells from chemotherapy-induced apoptosis. Here we review recent work undertaken in our laboratory addressing this issue. We have shown that, in vivo, SCLC cells are surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites which contains, among other proteins, fibronectin, laminin and collagen IV. Furthermore, adhesion of SCLC cells to fibronectin, laminin and collagen IV through beta1 integrins enhances tumorigenicity and confers resistance to apoptosis induced by standard chemotherapeutic agents, including etoposide, cis-platinum and adriamycin. Adhesion to ECM proteins stimulated protein tyrosine kinase (PTK) activity in both untreated and etoposide-treated cells. This effect could be completely blocked by a selective PTK inhibitor or by a function-blocking beta1 integrin antibody. PTK activation was found to block chemotherapy-induced activation of the death protease caspase-3 and, hence, apoptosis. Adhesion to ECM or treatment with a PTK inhibitor did not affect etoposide inhibition of topoisomerase II. Thus adhesion to ECM through beta1 integrins protects SCLC cells from chemotherapy-induced caspase-3 activation and apoptosis by activating PTK signalling downstream of DNA damage. Survival of tumour cells attached to ECM within this microenvironment could explain the local recurrence of SCLC and other tumours that is often seen clinically after chemotherapy.
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PMID:Extracellular matrix regulation of drug resistance in small-cell lung cancer. 1191 4

Tryprostatin A 1 and B 2 are indole alkaloid-based fungal products that act in the G2/M phase of the cell cycle. Tryprostatin A and B as well as their two enantiomers and four diastereomers have been synthesized via a common strategy. As a measure of cytotoxicity, these eight stereoisomers were assayed for their growth inhibitory properties in human breast, prostate, and lung cancer cell lines. The ability of the tryprostatins and the tryprostatin stereoisomers to induce topoisomerase II-mediated DNA relaxation or to inhibit tubulin polymerization was also examined. Although none of the stereoisomers were significantly active in topoisomerase II- or tubulin-based assays, ds2-try B 11 was found to exhibit a cytotoxicity profile more potent than etoposide 3 in the human cancer cell lines examined. In addition, ds2-try B 11 is comprised of an L-tryptophan derivative coupled to a D-proline moiety, the latter stereochemistry of which may enhance the activity of 11 and potential analogues in vivo.
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PMID:Biological activity of the tryprostatins and their diastereomers on human carcinoma cell lines. 1193 9

The DNA topoisomerase inhibitor irinotecan (CPT-11, Camptosar) is being evaluated as a novel chemotherapeutic agent that may complement other agents and treatment modalities for small-cell lung cancer (SCLC). Combination chemotherapy is the most effective means of improving the survival of patients with extensive disease, but until recently, no combination demonstrated superior efficacy. In a recent Japanese phase III study, irinotecan in combination with cisplatin significantly improved the survival of previously untreated patients with extensive SCLC compared to standard etoposide/cisplatin therapy (median progression-free survival: 6.9 vs 4.8 months, P = .003; median overall survival: 12.8 vs 9.4 months, P = .002). Two additional phase III trials have been planned in the United States to confirm these results, and to investigate how the administration schedule of irinotecan/cisplatin may be modified to improve its therapeutic index. The results of phase I/II studies have shown that other irinotecan-based combinations demonstrate promising activity in this disease as both first- and second-line therapy. This article reviews the rationale for the use of irinotecan in SCLC, examines key findings from recent clinical studies of irinotecan-based therapy, and discusses how the use of irinotecan in combination with new noncytotoxic anticancer agents can and will be further explored.
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PMID:Irinotecan therapy for small-cell lung cancer. 1201 33


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