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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The investigational antineoplastic agent, taxol, a natural product from the yew, Taxus sp. L., is currently being evaluated in a series of Phase II clinical trials. To date, the drug has shown activity against ovarian cancer, lung cancer, and melanoma. Taxol is a potent microtubule stabilizing agent that selectively blocks cells in the G2 and M phases of the cell cycle and is cytotoxic in a time-concentration dependent manner. It is well known from radiobiological principles that G2 and M are the most radiosensitive phases of the cell cycle. On the rationale that taxol could function as a cell-cycle selective radiosensitizer, we examined the consequences of combined drug-radiation exposures on the human grade 3 astrocytoma cell line, G18. Survival curve analysis shows a dramatic interaction between taxol and ionizing radiation with the degree of enhanced cell killing dependent on taxol concentration and on the fraction of cells in the G2 or M phases of the cell cycle. The sensitizer enhancement ratio (SER) for 10 nM taxol at 10% survival is approximately 1.8. These results obtained with cycling aerated radioresistant brain tumor cells indicate that significant advantage may derive from appropriate time-concentration dependent interactions in combined modality protocols.
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PMID:Taxol: a novel radiation sensitizer. 134 33

Taxol, an agent with a unique mechanism of action, has been shown to be highly active in patients with refractory ovarian cancer and may well have significant activity in other malignancies such as breast and lung cancer. The camptothecin analogs, another unique class of agents, have demonstrated antitumor activity in phase I and II trials. Finally, the anthrapyrazoles are intercalating agents with clinical activity in breast cancer and a toxicity profile that may permit increased dose intensity using colony-stimulating factor support. While this review focuses on these three drug classes, a number of other agents with apparently unique mechanisms of antitumor activity and unusual dose-limiting toxicities are in earlier development. These include antimetabolites; inhibitors of DNA, RNA, or protein synthesis; differentiating agents; agents that inhibit tumor growth by binding to growth factors; and agents whose mechanism of action is best classified as unknown.
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PMID:New anticancer agents: taxol, camptothecin analogs, and anthrapyrazoles. 136 58

Taxol is a unique mitotic inhibitor that has entered phase II investigation. Phase I studies demonstrated hypersensitivity reactions that were related to the cremophor vehicle and to the rate of drug infusion. As a result, the time span of intravenous (IV) infusion of taxol was routinely prolonged to 6 hours or beyond, and premedication with diphenhydramine, dexamethasone, and cimetidine was initiated. Early studies showed antitumor activity, especially against malignant melanoma and ovarian carcinoma. This phase I trial was performed giving taxol, as a 6-hour IV infusion every 21 days, without premedication. The purpose was to study the necessity of premedication and its impact on toxicity and pharmacokinetics. Thirty-one patients received 64 assessable courses of taxol. One patient had a hypersensitivity reaction, which was easily controlled using routine measures. Myelosuppression was dose-limiting, but sporadic, with two fatalities due to sepsis. Nonhematologic toxicity was of grade 1 and 2 except for one patient with grade 3 mucositis and two patients with grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias, requiring discontinuation of drug in two patients. Four partial responses were seen (three in patients with non-small-cell lung cancer, one in a patient with adenocarcinoma of unknown primary). Pharmacokinetic values were consistent with those previously reported. The occurrence of myelosuppression or neurotoxicity appeared to be associated with the area under the concentration x time curve (AUC) of taxol. The recommended phase II starting dose on this schedule is 225 mg/m2. Taxol merits broad investigation at the phase II level.
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PMID:A phase I trial of taxol given by a 6-hour intravenous infusion. 167 63

Sequential chemotherapy and radiotherapy offer considerable improvements in the care of patients with locally advanced non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). Improved survival for lung cancer and organ preservation in head and neck cancer have occurred with this approach, but local control remains a problem. Concurrent chemotherapy and radiotherapy can potentially improve both local control and control of micrometastases. We previously showed that concurrent carboplatin plus radiotherapy is a useful potential treatment for advanced NSCLC and SCCHN, producing good local control and acceptable toxicity. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has recently demonstrated strong single-agent activity against both NSCLC and SCCHN. Paclitaxel has also shown favorable interactions with radiotherapy and with platinum compounds. We therefore added weekly paclitaxel at 45 mg/m2 given after premedication and before carboplatin (100 mg/m2) weekly during concurrent standard-dose radiotherapy. Twenty patients (seven with SCCHN and 13 with NSCLC) have been treated (38 and 73 weekly doses, respectively). Toxicities have been manageable with delay or dose reduction in five and eight patients, respectively, for SCCHN and NSCLC. Based on these toxicities paclitaxel dose has been reduced to 40 mg/m2/wk. Plasma pharmacokinetics have shown that concurrent carboplatin and radiotherapy do not alter the pharmacokinetic behavior of paclitaxel compared with single-agent data. Concurrent therapy with carboplatin, paclitaxel, and radiotherapy is feasible on this schedule. Further case accrual to assess efficacy is ongoing.
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PMID:Feasibility and pharmacokinetics of paclitaxel, carboplatin, and concurrent radiotherapy for regionally advanced squamous cell carcinoma of the head and neck and for regionally advanced non-small cell lung cancer. 748 56

Taxol is a novel anticancer agent with activity against a broad range of tumors. It has a unique ability to stabilize polymerized tubulin into microtubule bundles within the cell. We have established a taxol-resistant human small-cell lung cancer cell line (H69/Txl) by exposing H69 cells to stepwise increases in taxol concentration. The resistance of H69/Txl cells to taxol was 4.7-fold that of the original H69 cells: the IC50 values for H69 and H69/Txl were 113.7 +/- 56.54 nM and 538.7 +/- 214.7 nM by the tetrazolium dye assay, respectively. Removal of the drug from the medium resulted in a 38% decrease in the growth rate of H69/Txl as compared with that in the presence of 30 nM taxol, suggesting that the growth of H69/Txl was partially dependent on taxol. H69/Txl showed higher sensitivity to vinca alkaloids such as vindesine, vincristine and vinblastine than the parental H69. There was no significant difference in intracellular [3H]taxol content between H69 and H69/Txl cells. No MDR-1 mRNA was detected in H69/Txl by the reverse transcription polymerase chain reaction. There was no significant difference of total and polymerized tubulin content between H69 and H69/Txl cells. Altered mobility of one of the alpha-tubulin isoforms in H69/Txl was revealed by using isoelectric focusing and Western blotting with anti-alpha-tubulin antibody. In H69, two alpha-tubulin isoforms were observed, whereas three were evident in H69/Txl, two of them comigrating with the isoforms of H69 and the other being more acidic. We observed the increased acetylation of alpha-tubulin in H69/Txl cells as compared with that in H69 cells. The acetylation of alpha-tubulin may be responsible for the taxol resistance and/or taxol-dependent growth of H69/Txl.
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PMID:Characterization of a taxol-resistant human small-cell lung cancer cell line. 751 86

Lung cancer cell lines are between seven and 1,000 times more sensitive to paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) when exposed for 120 hours (5 days) compared with 3-hour exposure. A phase I study of 4-day infusion of paclitaxel plus bolus cisplatin for patients with lung cancer has defined the recommended phase II dose. In this study, paclitaxel infused at 30 mg/m2/d for 4 days followed by a cisplatin bolus of 80 mg/m2 after infusion completion was associated with acceptable hematologic toxicity. Nine of the 16 patients with non-small cell lung cancer treated with at least two cycles of this regimen attained an objective tumor response (one complete response and eight partial responses; overall response rate, 56%). The recommended phase II dose of a 4-day infusion of paclitaxel plus bolus cisplatin followed by the administration of granulocyte colony-stimulating factor has not yet been determined.
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PMID:Four-day paclitaxel infusion with cisplatin for patients with lung cancer. 754 27

A phase I study was conducted to define the maximally tolerated dose and toxicity profile of the ifosfamide/carboplatin/etoposide/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (ICE-T) regimen in advanced lung cancer. This chemotherapy program uses paclitaxel given as a 24-hour continuous infusion in conjunction with full-dose ICE chemotherapy with growth factor support. The dosage of paclitaxel was escalated from 75 to 225 mg/m2. Thirty-four patients have been accrued to date onto this study. Because hematologic dose-limiting toxicity was defined in terms of neutropenia and/or thrombocytopenia exceeding 7 days' duration, no patient demonstrated what was defined by the protocol as dose-limiting toxicity. Nonetheless, substantial hematologic toxicity was observed. Overall, 26% had fever and neutropenia, 56% had grade 4 neutropenia, and 26% had grade 4 thrombocytopenia. In all cases, hematologic toxicity was short term and reversible. While grade 3 and 4 myelosuppression was frequently observed, it was not dose related (in terms of paclitaxel dosage). Nonhematologic toxicity also was not dose related and, with only a few exceptions, was not clinically significant. Among 27 patients evaluable for response, 41% achieved an objective response, including 15% with a complete response. All of five patients with small cell lung cancer responded (including two with a complete response). Among 22 patients with non-small cell lung cancer, 27% achieved an objective response (also including two with a complete response). The results of this study suggest that with growth factor support, it is possible to safely administer full-dose, single-agent paclitaxel in conjunction with full-dose ICE chemotherapy. We will soon be initiating a phase II study of the ICE-T regimen using paclitaxel at 225 mg/m2 as a 24-hour continuous infusion in advanced lung cancer. We will also conduct a phase I study of ICE-T, with paclitaxel administered as a 3-hour continuous infusion.
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PMID:A phase I study of ifosfamide/carboplatin/etoposide/paclitaxel in advanced lung cancer. 754 29

Paclitaxel (Taxol), the prototype of a new class of plant-derived antineoplastic compounds, is a natural product isolated from the Pacific yew. Docetaxel (Taxotere) is a hemisynthetic product derived from the European yew. These agents share a unique mechanism of cytotoxic action by promoting assembly of microtubules and rendering the microtubules resistant to depolymerization. In vitro studies suggest a possible role for radiation sensitization. In Phase I trials, the dose-limiting toxicity was neutropenia for both agents. Other toxicities include infusion-related hypersensitivity reactions, alopecia, neurotoxicity, mucositis, diarrhoea and myalgias. To prevent infusion-related reactions, routine premedication is recommended. Noncumulative cardiac toxicity has been observed with paclitaxel. Fluid retention and rash have been reported with docetaxel. In Phase II studies of paclitaxel in advanced non-small cell lung cancer, response rates of 21% and 24% were observed. In Phase II studies of docetaxel in similar patients, response rates ranging from 28-38% were reported, including patients previously treated with cisplatin. The most common toxicity in these studies was neutropenia. Combination studies with cisplatin and other agents are in progress. Paclitaxel and docetaxel are among the most active chemotherapeutic agents for non-small cell lung cancer patients. Their testing will dominate trials of new therapies in this disease for years to come.
Lung Cancer 1995 Apr
PMID:Paclitaxel (Taxol) and docetaxel (Taxotere): active chemotherapeutic agents in lung cancer. 755 25

We conducted a phase I trial in advanced NSCLC to determine the optimal dosage of the new active drug paclitaxel (Taxol), in combination with high-dose ciplastin (CDDP). Taxol was infused over 3 h, followed by CDDP given over 30 min with hyperhydration. Main criteria of selection were the presence of metastatic or locally relapsing pathologically proven NSCLC, stage IIIB or IV and no prior therapy. Out of 17 treated patients, eight objective responses (47%) were documented. Significant but transient neutropenia was observed in steps III and IV. In seven patients, who received more than three courses, treatment was discontinued for severe polyneuropathy in five, cancer progression in one and unrelated disease in one. In conclusion, paclitaxel plus cisplatin, although active, was associated with severe late neurological toxicity prohibiting the administration of multiples courses.
Lung Cancer 1995 Jun
PMID:Dose-finding study of paclitaxel (Taxol) plus cisplatin in patients with non-small cell lung cancer. European Lung Cancer Working Party. 755 43

Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-related death in the United States. Only about 30% of patients present with surgically resectable (and thus curable) disease. Because existing chemotherapeutic regimens are never curative in advanced NSCLC and because the median survival time is only modestly increased, the Eastern Cooperative Oncology Group (ECOG) has concentrated on a broad phase II testing program designed to identify new agents with activity against the disease. Of the more than one dozen drugs that have been thus evaluated during the past 10 years, only paclitaxel (Taxol) has been shown to result in an objective response rate of more than 20%. To determine if the paclitaxel-containing regimen can increase survival, ECOG has, therefore, embarked on a phase III trial (E5592) in which patients with stage IV NSCLC are randomly assigned to receive either cisplatin plus etoposide (the current standard chemotherapy) or cisplatin plus paclitaxel. The trial design should also help to determine the appropriate dose of paclitaxel in this clinical setting.
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PMID:Phase III trial (E5592) comparing cisplatin plus etoposide with cisplatin plus paclitaxel at two dose levels for treatment of advanced non-small-cell lung cancer. Eastern Cooperative Oncology Group. 757 8


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