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)

Topoisomerase I inhibitors have demonstrated significant activity in non-small-cell lung cancer. In phase II studies, particularly in Japan, single-agent irinotecan (Camptosar, CPT-11) has produced response rates as high as 35%. In combinations with cisplatin (Platinol), it has also resulted in overall response rates of 41% to 52%, with median survival of 10.2 to 13 months, and 1-year survival rates of 33% and 58%. A Japanese phase III randomized trial of irinotecan, either alone or in combination with cisplatin vs vindesine/cisplatin in previously untreated stage IIIB/IV non-small-cell lung cancer, demonstrated that survival among stage IV patients was significantly better in the irinotecan arms compared to the vindesine/cisplatin group. However, another Japanese phase III study comparing irinotecan/cisplatin to vindesine/cisplatin failed to show a survival difference. Initial North American efforts recapitulated this work, while a follow-up study incorporated weekly irinotecan with weekly cisplatin, yielding a response rate of 36%, median survival of 11.6 months, and a 1-year survival rate of 46%. Irinotecan/taxane combinations have also shown promise. Phase I/II studies in advanced non-small-cell lung cancer with paclitaxel (Taxol), irinotecan, and carboplatin (Paraplatin) produced a response rate of 38%, median survival of 11 months, and a 1-year survival rate of 47%; other trials with irinotecan and paclitaxel are ongoing. Phase I data for irinotecan/docetaxel (Taxotere) have indicated an overall response rate of 32%, median survival of 39 weeks, and a 1-year survival rate of 38%; subsequent phase II trials used either cisplatin or irinotecan in combination with docetaxel and yielded a promising median survival of 45.6 weeks, comparable to the standard cisplatin/docetaxel combination. Phase I trials with irinotecan and gemcitabine (Gemzar) have also yielded promising results. Follow-up efforts include phase II studies in both chemonaive advanced non-small-cell lung cancer and progressive small-cell lung cancer (salvage therapy). Clearly, clinical trial data have demonstrated the utility of irinotecan in the treatment of advanced non-small-cell lung cancer. Planned combinations with new chemotherapeutic agents and biological response modifiers may provide additional treatment options.
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PMID:Treatment of non-small-cell lung cancer in North America: the emerging role of irinotecan. 1122 Oct 17

Gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), and vinorelbine (Navelbine) are among the most active agents for the treatment of non-small-cell lung cancer and are generally more active than platinum compounds. When combined with a platinum compound, these agents have produced the best survival outcomes seen to date in non-small-cell lung cancer. More than 100 clinical trials have defined and expanded the role of gemcitabine, which has been combined with each of these agents to create novel combinations. Several new nonplatinum-based combinations compare favorably with platinum-based combinations with respect to toxicity and efficacy. Moreover, changing the schedule of gemcitabine administration from days 1, 8, 15 every 4 weeks to days 1 and 8 every 3 weeks seems to allow greater dose intensity with less severe toxicity and slightly greater efficacy. Coadministration of docetaxel, paclitaxel, or vinorelbine with gemcitabine on days 1 and 8 every 3 weeks is a promising approach. In addition to a lower incidence of severe neutropenia, docetaxel, paclitaxel, and vinorelbine protect against gemcitabine-associated thrombocytopenia.
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PMID:Gemcitabine and nonplatinum combinations in non-small-cell lung cancer. 1130 44

Current agents for the treatment of non-small-cell lung cancer include gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and irinotecan (CPT-11, Camptosar). Experimental agents include pemetrexed (LY231514, Alimta) and tirapazamine. Molecular and biological therapies include angiogenesis inhibitors, epidermal growth factor receptor inhibitors, HER2/neu inhibitors, and inhibitors of ras activation and function. Doublet chemotherapy is currently the standard treatment for advanced non-small-cell lung cancer. In the past 2 years, randomized trials have shown that many of the new two-drug combinations used to treat non-small-cell lung cancer have equivalent efficacy. These combinations produce 1-year survival rates of about 35% and 2-year survival rates of about 15%. Toxicity rates vary but are sufficiently low as to make the development of three-drug combinations feasible. Preliminary studies from several phase I and II trials suggest that triplet therapy can improve survival beyond that of double therapy regimens.
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PMID:Triplet combination chemotherapy and targeted therapy regimens. 1130 45

Platinum-based chemotherapy regimens have been the mainstay of treatment for non-small-cell lung cancer because they improve survival. Although there is no standard platinum-based regimen, combination regimens with newer agents (e.g., gemcitabine [Gemzar], paclitaxel [Taxol], and vinorelbine [Navelbine]) are superior to platinum alone or in combination with older agents (e.g., etoposide). Four phase III clinical studies demonstrate the favorable activity and toxicity profile of gemcitabine in combination with cisplatin (Platinol) for the treatment of patients with stage IIIB or IV non-small-cell lung cancer. These studies show overall response rates of approximately 30% to 60% with gemcitabine regimens versus overall response rates of 11% with cisplatin alone, 22% with cisplatin plus etoposide, 25% with cisplatin plus vinorelbine, and 40% with cisplatin plus mitomycin and ifosfamide (Ifex). Median survival time with gemcitabine regimens ranged from 8.1 to 9.8 months. Thrombocytopenia and anemia are the principal toxicities with gemcitabine regimens. Because of the favorable results with gemcitabine regimens, this drug is being evaluated in combination with carboplatin (Paraplatin) in newly diagnosed patients with stage IIIB or IV disease and good performance status, or as single-agent therapy in patients with poor performance status.
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PMID:Gemcitabine for the treatment of non-small-cell lung cancer. 1130 46

Gemcitabine (Gemzar) has demonstrated activity in a broad range of solid tumors with good tolerance. In combined-modality therapy, gemcitabine has achieved response rates ranging between 30% and 60% in patients with non-small-cell lung cancer. Initial trials of gemcitabine and radiation showed that the fields and volume of radiation as well as the dose of gemcitabine should be managed carefully so as to optimize the radiosensitizing properties of this agent. The Cancer and Leukemia Group B conducted a phase III trial in patients with unresectable stage III non-small-cell lung cancer. A total of 187 patients were randomized to one of three cisplatin (Platinol)-based combinations (with gemcitabine, paclitaxel [Taxol], or vinorelbine [Navelbine]) as induction therapy followed by concomitant chemoradiation. At a median follow-up of 9 months, the median survival for all patients was 18 months and the median progression-free survival was 10 months. The trial demonstrated that the combination of gemcitabine and cisplatin could be administered successfully as induction therapy without affecting concurrent administration of gemcitabine/cisplatin with radiation.
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PMID:Optimizing chemoradiation in locally advanced non-small-cell lung cancer. 1130 48

During the past decade, five new cytotoxic drugs have been introduced that are active against non-small-cell lung cancer (NSCLC). These agents include vinorelbine (Navelbine), paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine (Gemzar), and irinotecan (CPT-11, Camptosar). Used alone, these drugs display activity comparable to cisplatin. The combination of cisplatin and one of the newer drugs produces better survival than treatment with cisplatin (Platinol) alone. Randomized studies of chemotherapy regimens that include these newer drugs have demonstrated improved survival, fewer side effects, or both, compared with earlier standard combinations such as cisplatin/vindesine or cisplatin/etoposide. Docetaxel and perhaps some of the other newer drugs are of value for patients previously treated with platinum-containing regimens. Future studies should determine whether combinations of these newer drugs are superior to cisplatin-containing regimens. Although improved survival is the most important factor in defining the best regimen in non-small-cell lung cancer, additional considerations include patient tolerability, costs of administration, and the rationale for and ability to include noncytotoxic agents (such as inhibitors of signal transduction pathwriys or angiogenesis) into the therapeutic program.
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PMID:Rationale for non-platinum chemotherapy in advanced NSCLC. 1149 29

Non-small cell lung cancer (NSCLC) is a systemic illness. The majority of newly diagnosed patients depend on systemic chemotherapy to improve outcome. Among the new chemotherapeutic agents recently tested, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown convincing single-agent activity in advanced NSCLC. The two initial phase II studies using paclitaxel alone showed a 1-year survival rate of 40%, comparable to that seen with combination regimens. Paclitaxel/carboplatin is one of several standard regimens for patients with stage IIIB to IV disease. It is as effective as any other new agent/platinum combination studied to date; it is easy to administer and well tolerated. Identification of the molecular and genetic events involved in each step of tumor progression seems to be crucial both to understanding lung cancer and for the development of new pharmacologic compounds that target specific cellular processes affecting growth and proliferation. An innovative strategy is to combine established chemotherapy with these new compounds. Resistance to available chemotherapy drugs is the major obstacle to effective chemotherapy. Genetic abnormalities could play a role in outlining some patterns of chemoresistance. Acquired resistance to paclitaxel can be mediated by several mechanisms, including overexpression of p-glycoprotein, altered expression of beta-tubulin isotypes, intrinsic or acquired mutations in beta-tubulin, and expression of novel genes. Beta-tubulin mutations were recently identified in 33% of 49 NSCLC patients, none of whom had an objective response to paclitaxel treatment. Cisplatin resistance is associated with several molecular alterations, including overexpression of metallothionein and the mRNA level of the excision repair cross-complementing (ERCC1) gene. Early detection of circulating cancer cells in peripheral blood would enable more accurate lung cancer staging. Furthermore, sequential measurements of DNA concentration may be used to monitor the effects of therapy. Serum DNA can be used as a surrogate for detecting genetic abnormalities and as a potential guide for customizing treatment. We analyzed the presence of beta-tubulin mutations in serum DNA from NSCLC patients and from healthy individuals. Beta-tubulin mutations were detected in 42% of the 131 patients and in none of the control group. Several clinical studies are proposed to develop more customized approaches in lung cancer.
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PMID:Predicting response to paclitaxel/carboplatin-based therapy in non-small cell lung cancer. 1160 82

A series of Taxol derivatives tethered at C2' and C-7 to glutamate and folate have been synthesized for evaluation as prodrugs which release Taxol via hydrolytic lability of their alpha-alkoxy and alpha-amino esters. The half-time for hydrolysis of these materials was determined in pH 7 and pH 5 buffer. The in vitro cytotoxicity has been assessed in cell culture against A-549 lung cancer, MCF-7 breast cancer, and HT-29 colon cancer. Selected agents were further screened for folate binding and competitive binding with free folic acid. One agent (54), further evaluated in animal studies was found to increase the lifespan in mice, but was less effective than Taxol itself.
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PMID:Synthesis and evaluation of taxol-folic acid conjugates as targeted antineoplastics. 1198 37

The antitumor efficacy of the combination of nedaplatin (NDP) with gemcitabine (GEM) was evaluated against Ma44/GEM, a GEM-refractory subline of Ma44 human lung cancer, which was established by serial in vitro passage of Ma44 cells in the presence of GEM.Ma44/GEM showed less sensitivity to GEM and cytosine arabinoside with resistance factors of 7.7 and 8.3, respectively, but not to Taxol, Irinotecan, Mitomycin C and NDP. Flow cytometry analysis demonstrated that membrane transporter molecules such as multidrug-resistant, multidrug-resistant related protein or lung resistant protein were not induced in Ma44/GEM cells. In vivo experiments confirmed the less sensitivity of Ma44/GEM to GEM. The resistant factor of Ma44/GEM to GEM in vivo was estimated to be 6.7 in terms of ED(50).MA44/GEM-implanted athymic mice were treated with GEM i.v. once followed by i.v. injection of NDP at an interval of approximately 30 min. The mice were treated again with GEM after 3 or 4 days. The combined dosing of NDP with GEM resulted in synergistically enhanced inhibition of tumor growth against Ma44/GEM. The antitumor efficacy of the combination of NDP and GEM was superior to the best effect of either monotherapy. These results demonstrate the effectiveness of the combination of NDP with GEM against the GEM-refractory human lung cancer model.
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PMID:Preclinical combination chemotherapy of nedaplatin with gemcitabine against gemcitabine-refractory human lung cancer. 1217 24

Paclitaxel (PTX, Taxol) has revolutionized cancer treatment in the past decade and is recognized as one of the biggest advances in oncology medicine. In spite of the good clinical efficacy shown by PTX, there is still a growing need to achieve better safety and pharmacokinetic profile of PTX in patients. The standard delivery modalities of intravenous infusion result in multiple side effects, and targeting of the drug to specific areas within the body can result in better efficacy and lower toxicity. Aerosol delivery of therapeutic agents has the potential of localizing the drugs specifically to the lung tissue, with a comparable or better pharmacokinetics as compared to intravenous, oral or intraperitoneal delivery. Aerosol delivery of PTX has not been studied extensively, however, it holds immense potential for improving the efficacy against lung tumors. Early pre-clinical studies in mice and dogs have shown good promise, both for pharmacokinetics of PTX, safety and efficacy in lung cancer models. This review looks at the still developing approach of aerosol delivery of PTX for lung cancer, documents the progress so far and the future directions that can bring this approach to clinical reality.
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PMID:Paclitaxel (taxol) and taxoid derivates for lung cancer treatment: potential for aerosol delivery. 1287 Oct 59


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