Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0684249 (lung carcinoma)
23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Historically, the treatment of advanced non-small cell lung cancer (NSCLC) with cisplatin-based therapy has been a nearly futile effort. Median survival was seldom greater than six months, and fewer than 20% of those with metastatic NSCLC survived more than one year. In addition, toxicity often equaled, if not exceeded, benefit. Over the past five years, however, we have witnessed an explosion of new agents in advanced lung carcinoma. These new agents-in particular the taxanes, gemcitabine, vinorelbine, and topoisomerase I inhibitors-have breathed new life into clinical research. The therapeutic gains, though modest, are real. Paclitaxel, to a large extent, given either alone or in combination with platinols, has led the charge.
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PMID:The Burgeoning Role of Paclitaxel in Advanced Pulmonary Malignancy. 1038 88

A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in clinical trial, show superior potencies to the corresponding monomeric DACA analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JLC. Larger substituents at any position caused a steady decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurkat lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.
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PMID:Structure-activity relationships for substituted bis(acridine-4-carboxamides): a new class of anticancer agents. 1039 79

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA), a DNA intercalating dual topoisomerase I/II poison, has high experimental antitumour activity, is able to overcome several forms of multidrug resistance, and is undergoing clinical trial. We prepared 3H-labelled DACA and investigated its uptake using cultured Lewis lung carcinoma cells (LLTC), P388 leukaemia cells and P/DACT cells that were multidrug resistant. The kinetics of uptake and efflux were very rapid and equilibrium was obtained within seconds of drug addition. Fluorescence microscopy of LLTC cells treated with DACA showed punctate fluorescence in the cytoplasm, consistent with uptake into vesicles. To investigate the role of lipophilicity in drug uptake, a fluorimetric assay was developed to measure uptake of a more hydrophilic derivative, 9-amino-5-sulphonylmethyl-DACA (as-DACA). The calculated n-octanol-water partition coefficient for as-DACA was 20-fold lower than that for DACA. On the other hand, as determined by ethidium displacement from DNA, as-DACA bound DNA 16-fold more strongly than did DACA. Uptake and efflux of DACA and as-DACA were very rapid and the uptake ratios in LLTC cells were 550 for DACA and 54 for as-DACA. At equitoxic concentrations (corresponding to the IC50 values), LLTC cell association was estimated to be approximately 1.6 x 10(8) molecules per cell for DACA and 3.0 x 10(6) molecules per cell for as-DACA. It is argued that DACA binds predominantly to lipophilic sites such as proteins and cellular membranes, while as-DACA associates predominantly with DNA. The high affinity of DACA for membranes may contribute to the rapidity of its uptake and efflux, as well as to its ability to overcome multidrug resistance.
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PMID:Cellular uptake of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). 1050 May 2

An important component in the development of a new anticancer drug is an understanding of its potential for inclusion in combination treatment regimens. LY231514, a multitargeted antifolate (MTA), was tested in combination with cisplatin, methotrexate, 5-fluorouracil, paclitaxel, docetaxel, doxorubicin, LY329201 (a glycinamide ribonucleotide formyltransferase [GARFT] inhibitor), and fractionated radiation therapy in vivo using EMT-6 mammary carcinoma, human HCT 116 colon carcinoma, and human H460 nonsmall cell lung carcinoma grown as xenografts in nude mice. Isobologram methodology was used to determine the additivity or synergy of the combination regimens. MTA administered with cisplatin, paclitaxel, docetaxel, or fractionated radiation therapy produced additive to greater than additive tumor response by tumor cell survival assay and tumor growth delay. While an additive tumor response was observed when MTA was administered with methotrexate, synergistic tumor responses were seen when MTA was administered with the GARFT inhibitor, LY329201, or with the topoisomerase I inhibitor, irinotecan. MTA was administered in combination with full doses of each anticancer agent studied, with no evidence of increased toxicity resulting from the combination.
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PMID:MTA (LY231514) in combination treatment regimens using human tumor xenografts and the EMT-6 murine mammary carcinoma. 1059 56

Topotecan, a soluble semisynthetic derivative of camptothecin, is a specific inhibitor of topoisomerase I and is endowed of potent antiproliferative effect in vitro and in vivo on tumoral cell lines as well as on endothelial cells. Moreover, topotecan is able to interfere with the development of blood vessels in many in vivo experimental models. During the last years, several phase I clinical studies have demonstrated that the five-daily schedule is the most effective for the treatment of neoplastic diseases of children and adults. In particular, the best clinical results have been obtained in patients affected by metastatic ovarian cancer, small cell (SCLC) and non-small cell lung carcinoma (NSCLC), as well as mammary and gastrointestinal neoplasms. High response rates have been observed in myelodysplastic syndromes and myeloma. The clinical effectiveness of topotecan has been also demonstrated in ovarian carcinoma, even after failure of first or second line chemotherapy and in SCLC, where the response rate is 39%, while the percentage decreases up to 7% in case of drug resistance, with a median survival of 5.4 months. Toxicologic profile of topotecan is foreseeable and manageable, and the most frequent and severe toxicity is represented by myelosuppression. Leukopenia and neutropenia, which follow the administration of topotecan, are non-cumulative and self-limiting and unfrequently complicated by infections, whereas non-hematologic toxicities are uncommon and generally of mild-to-moderate degree. Topotecan is under continuous clinical evaluation for the treatment of neoplasms other than those reported above, alone or in combination with antineoplastic drugs in poly-chemotherapeutic protocols.
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PMID:[Preclinical pharmacology and clinical uses of topotecan]. 1078 94

The treatment of advanced non-small cell lung carcinoma (NSCLC) has improved greatly over the past decade. With the advent of new agents, in particular taxanes, gemcitabine, vinorelbine, and topoisomerase I inhibitors, response rates have improved from 15-20% to 25-35%, with commensurate improvement in median and one year survival rates to 8-10 months and 35-45%, respectively. These improvements have proven statistically significant in multiple studies [1-4]. Docetaxel, either alone or in combination with platinols, has shown particular promise; and, in some arenas, it has become a standard component of our therapeutic armamentarium. We will review the preclinical data and single agent activity of docetaxel in treatment-naive and previously treated NSCLC patients, its activity in combination with cisplatin and carboplatin, as well as other new agents, and finally focus on ongoing studies evaluating its role in locally advanced disease.
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PMID:Advanced non-small cell lung carcinoma: the emerging role of docetaxel. 1083 Jan 38

Deoxynybomycin was identified as an inducer of p21the/WAF1 gene following screening using a reporter, p21/luciferase. The present study examined its anti-proliferative effect on human tumor cell lines. Deoxynybomycin selectively inhibited growth of human osteoblastic sarcoma Saos-2, gastric cancer TMK-1, and monocytic leukemia THP-1 cells, but did not affect survival of normal human fibroblasts at doses up to 5 microg/ml. Results from an assay system using a panel of 39 human cancer cell lines indicated that deoxynybomycin has selective cytotoxic activity against lung carcinoma cell lines. Deoxynybomycin induced apoptosis in Saos-2, TMK-1, and THP-1 cells as revealed by DNA fragmentation and TUNEL assays. It inhibited topoisomerase I but not topoisomerase II. These results suggest that deoxynybomycin may be useful in cancer chemotherapy.
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PMID:Deoxynybomycin is a selective anti-tumor agent inducing apoptosis and inhibiting topoisomerase I. 1099

Patients with limited-stage small-cell carcinoma of the lung are treated with combined-modality therapy with the intent to cure. Standard therapy consists of platinum-based combination chemotherapy, thoracic irradiation, and for responders, prophylactic cranial irradiation. Despite this aggressive approach, too few patients achieve 5-year survival. In the past several years, new chemotherapeutic agents, including the taxanes and the topoisomerase I inhibitors, have demonstrated substantial activity against small-cell carcinoma. These agents are now being incorporated into clinical trials for patients with limited-stage disease. The best combination of these agents with platinum-based regimens is yet to be determined, and data supporting increased survival are awaited. Other studies are exploring thoracic radiation issues. Questions remain regarding optimal timing, dose, volume, and fractionation schemes. The most effective combination of thoracic irradiation and the newer chemotherapy agents also remains to be determined. The current approach to limited-stage small-cell carcinoma is reviewed, ongoing trials are described, and future directions are explored.
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PMID:Limited small-cell lung cancer: a potentially curable disease. 1109 5

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

In an attempt to synthesize potential anticancer agents acting by inhibition of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. The compounds were tested for their cytotoxic activity in vitro against H460 non-small lung carcinoma cell line, the activity being for 24 out of 37 compounds in the 0.01-0.3 microM range. A QSAR analysis indicated that lipophilicity is the main parameter correlated with cytotoxicity. Investigation of the DNA-Topo I-drug cleavable complex showed a rough parallelism between cytotoxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex suggests that for the most potent compounds, e.g., 15, the cytotoxicity was at least in part related to stabilization of the complex, as also supported by the persistence of the DNA-enzyme complex in drug-treated cells. The in vivo antitumor efficacy of the most potent analogue (15) was evaluated in direct comparison with topotecan using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibition of tumor growth and rate of complete response.
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PMID:Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity. 1156 25


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