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)

Taxol is extensively used clinically for chemotherapy of patients with ovarian, breast, and lung cancer. Although taxol induces apoptosis of cancer cells, its exact mechanism of action is not yet known. To determine the mechanism of action of taxol in ovarian cancer, we tested the effects of the drug, on the human ovarian carcinoma cell line, SKOV3. We observed that taxol-induced apoptosis of these cells by phosphatidylserine (PS) externalization and DNA fragmentation. While treatment of cells with taxol resulted in bcl-2 phosphorylation and mitochondrial depolarization, cytochrome c was not released and pro-caspase-3 was not activated. Treatment of SKOV3 cells with taxol, however, resulted in the translocation of AIF from the mitochondria to the nucleus via the cytosol. Taken together, these findings suggest that in SKOV3 cells, taxol induces caspase-independent AIF-dependent apoptosis.
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PMID:Mechanism of taxol-induced apoptosis in human SKOV3 ovarian carcinoma cells. 1503 38

Drug resistance is a fundamental problem in cancer chemotherapy. Intracellular calcium concentration ([Ca2+](i)) may play a role in the development of chemoresistance. We investigated the regulatory role of [Ca2+](i) in Taxol resistance in the non-small-cell lung cancer cell line A549 and its chemoresistant subclone A549-T24. Measurement of cytosolic calcium ([Ca2+](c)) in single cells and cell populations revealed similar levels of basal calcium in the two cell lines. However, a reduced response to thapsigargin (a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor) in A549-T24 cells compared to the parent cell line suggested a lower ER Ca2+ content in these cells. mRNA expression of SERCA2b and SERCA3, major Ca2+ pumps involved in ER Ca2+ homeostasis, did not significantly differ between the two cell lines, as revealed by RT-PCR. An altered calcium influx pathway in the Taxol-resistant cell line was observed. Modulation of the ER calcium pools using CMC (4-chloro-m-cresol) and ATP revealed lower ryanodine receptor (RyR) and IP(3) receptor (IP(3)R)-sensitive Ca2+ stores in the chemoresistant cell line. Western blot and RT-PCR studies suggested that A549-T24 cells expressed higher levels of the antiapoptotic protein Bcl-2 and the calcium-binding protein sorcin, respectively, in comparison to the parent cell line. Both of these proteins have been previously implicated in chemoresistance, in part, due to their ability to modulate[Ca2+](i). These results suggest that altered intracellular calcium homeostasis may contribute to the Taxol-resistant phenotype.
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PMID:Differential regulation of calcium homeostasis in adenocarcinoma cell line A549 and its Taxol-resistant subclone. 1506 2

Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a tumor necrosis factor superfamily member that induces apoptosis through the death receptors DR4 and/or DR5 in various cancer cell types but not in most normal cells. Several lung cancer cell lines express DR4 and DR5 and undergo apoptosis in vitro in response to Apo2L/TRAIL. We investigated the efficacy of recombinant soluble human Apo2L/TRAIL and its interaction with chemotherapy in xenograft models based on human NCI-H460 non-small cell lung carcinoma cells. In vitro, Taxol enhanced caspase activation and apoptosis induction by Apo2L/TRAIL. In vivo, Apo2L/TRAIL or Taxol plus carboplatin chemotherapy partially delayed progression of established subcutaneous tumor xenografts, whereas combined treatment caused tumor regression and a substantially longer growth delay. Apo2L/TRAIL, chemotherapy, or the combination of both inhibited growth of preformed orthotopic lung parenchymal tumors versus control by 60%, 57%, or 97%, respectively (all P < 0.01; n = 8-10). Furthermore, combination treatment improved day-90 survival relative to control (7 of 15 versus 1 of 15; P = 0.0003 by Mantel-Cox) as well as to Apo2L/TRAIL (3 of 14; P = 0.031) or chemotherapy (3 of 15; P = 0.035). These studies provide evidence for in vivo activity of Apo2L/TRAIL against lung tumor xenografts and underscore the potential of this ligand for advancing current lung cancer treatment strategies.
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PMID:Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. 1525 61

Paclitaxel (Taxol) has demonstrated clinical activity in non-small-cell lung cancer (NSCLC), but its use has not led to marked improvements in survival. This ineffectiveness can in part be attributed to inadequate delivery of effective drug levels to the lung via systemic administration and to drug resistance mechanisms. Locoregional drug administration and the use of drug copolymers are possible approaches to address these issues. In this study, we evaluated the activity of a poly(L-glutamic acid)-paclitaxel (PGA-TXL) formulation administered by intratracheal injection to mice bearing orthotopic human NSCLC tumors (H460, H358). H460 cells were found to be sensitive to paclitaxel and PGA-TXL in vitro, in a time- and concentration-dependent manner. In preliminary acute toxicity studies, PGA-TXL administered by intratracheal injection was found to be much less toxic than paclitaxel, as anticipated. Mice into which H460 cells had been implanted by intratracheal injection were given single-dose intratracheal treatments with paclitaxel (1.2 or 2.4 mg/kg) or with PGA-TXL (15 mg/kg, paclitaxel equivalents) 1 week later. When the mice were sacrificed at up to 65 days after tumor implantation, they were evaluated grossly for tumor at bronchial, neck, and lung sites. Control mice had tumors in 60% of all three sites, and all of the control mice had tumors in at least one site. The low- and high-dose Taxol groups had fewer incidences at these three sites (27-33%) and 60-80% of these mice had tumors in at least one site. The PGA-TXL mice displayed a low (13%) incidence at these sites, and only 40% had detectable tumors. In a subsequent survival study with the intratracheal H358 model, control mice had a mean life span of 95 days, whereas both the intratracheal Taxol (2.5 mg/kg, every 7th day for three doses) and the intratracheal PGA-TXL (20 mg/kg, paclitaxel equivalents, every 7th day for three doses) groups had improved survival (mean life spans: 133.5 and 136.5 days, respectively). In pilot studies intended to compare the feasibility of the development of paclitaxel aerosols suitable for clinical application, based either on Cremophor solutions or on PGA backbones, only the latter gave acceptable particle size distributions and flow rates. These results encourage the development and application of Cremophor-free copolymer formulations of paclitaxel for locoregional treatment (e.g., as aerosol) of endobronchial malignant diseases.
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PMID:Antitumor activity of hydrophilic Paclitaxel copolymer prodrug using locoregional delivery in human orthotopic non-small cell lung cancer xenograft models. 1553 15

Herbs have been considered natural and valuable sources for anticancer drug discovery. Herbal medicine has been prescribed in many countries over centuries for treating various diseases including infectious and malignant diseases. Nowadays, many of the drugs that have been used for treatment of malignant diseases are derived from natural products such as Taxol, a natural product isolated initially from Pacific Yew (Taxus brevifolia). This review article describes research on molecular mechanisms, especially cytotoxic effect of natural products from plant sources, primarily preclinical studies, involving human lung cancer cells in vitro for providing more knowledge and issues for potential drug development from medicinal herbs in the future.
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PMID:Molecular mechanism of herbs in human lung cancer cells. 1647 Nov 27

Induction chemotherapy may improve clinical outcome of locally advanced non-small cell lung cancer (NSCLC). To further pursue this, the Austrian Association for the Study of Lung Cancer (AASLC) performed a multi-center phase II trial with TIP induction chemotherapy (Taxol 175 mg/m2 over 3h on day 1, ifosfamide 1000 mg/m2 daily on days 1-3, cisplatin 60 mg/m2 on day 1, and prophylactic filgrastim 5 microg/kg daily on days 4-13). Treatment cycles were repeated every 3 weeks for 3 cycles. Then patients were re-staged and selected for local treatment. Forty-seven patients (33 male, 14 female; median age 58 years, range 36-78; 22 cIIIA, 25 cIIIB; 26 adenocarcinomas, 14 squamous cell carcinomas, 4 large cell carcinomas, 3 undifferentiated carcinomas) were included in this trial. Forty-five patients were evaluable for response and toxicity. An overall response rate of 43% (complete remission 4.5% and partial remission 38%) was achieved. Stable disease and progressive disease were seen in 38 and 15% of the patients, respectively. Down-staging occurred in 36% of the patients. The toxicities of the chemotherapy were mild and, in particular, no severe hematotoxicity was observed. Surgery was performed in 24 (51%) patients and resulted in complete tumor resection in 19 patients. Twenty-four patients received thoracic radiotherapy, 10 patients after surgery. Median survival was 10.3 months for the total population, 13.5 months for patients with cIIIA and 10 months for patients with clinical cIIIB. Survival was longer for patients with down-staging as compared to those without (median not reached versus 10 months, p=0.005) and for patients with complete tumor resection as compared to the remaining patients (27 months versus 10 months, p=0.05). In conclusion, the TIP regimen shows activity and good tolerance as induction chemotherapy in patients with locally advanced NSCLC.
Lung Cancer 2006 Oct
PMID:Induction chemotherapy with the TIP regimen (paclitaxel/ifosfamide/cisplatin) in stage III non-small cell lung cancer. 1692 60

Analysis of lung cancer response to chemotherapeutic agents showed the accumulation of a Taxol-induced protein that reacted with an anti-phospho-MEK1/2 antibody. Mass spectroscopy identified the protein as nucleophosmin/B23 (NPM), a multifunctional protein with diverse roles: ribosome biosynthesis, p53 regulation, nuclear-cytoplasmic shuttling, and centrosome duplication. Our work demonstrates that following cellular exposure to mitosis-arresting agents, NPM is phosphorylated and its chromatographic property is altered, suggesting changes in function during mitosis. To determine the functional relevance of NPM, its expression in tumor cells was reduced by siRNA. Cells with reduced NPM were treated with Taxol followed by microarray profiling accompanied by gene/protein pathway analyses. These studies demonstrate several expected and unexpected consequences of NPM depletion. The predominant downstream effectors of NPM are genes involved in cell proliferation, cancer, and the cell cycle. In congruence with its role in cancer, NPM is over-expressed in primary malignant lung cancer tissues. We also demonstrate a role for NPM in the expression of genes encoding SET (TAF1beta) and the histone methylase SET8. Additionally, we show that NPM is required for a previously unobserved G2/M upregulation of TAF1A, which encodes the rDNA transcription factor TAF(I)48. These results demonstrate multi-faceted functions of NPM that can affect cancer cells.
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PMID:Global functional analysis of nucleophosmin in Taxol response, cancer, chromatin regulation, and ribosomal DNA transcription. 1706 96

Paclitaxel (Taxol) is a frontline antineoplastic agent used to treat a variety of solid tumors including breast, ovarian, or lung cancer. The major dose limiting side effect of paclitaxel is a peripheral sensory neuropathy that can last days to a lifetime. To begin to understand the cellular events that contribute to this neuropathy, we examined a marker of cell injury/regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy; satellite cell hypertrophy in the dorsal root ganglia (DRG) and sciatic nerve as well as astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion, there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons and this up-regulation was present through day 10. In contrast, hypertrophy of DRG satellite cells, hypertrophy and hyperplasia of CD68(+) macrophages in the DRG and sciatic nerve, ATF3 expression in S100beta(+) Schwann cells and increased expression of the microglial marker (CD11b) and the astrocyte marker glial fibrillary acidic protein (GFAP) in the spinal cord were not observed until day 6 post-infusion. The present results demonstrate that using the time points and markers examined, DRG neurons show the first sign of injury which is followed days later by other neuropathological changes in the DRG, peripheral nerve and dorsal horn of the spinal cord. Understanding the cellular changes that generate and maintain this neuropathy may allow the development of mechanism-based therapies to attenuate or block this frequently painful and debilitating condition.
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PMID:An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. 1769 44

Paclitaxel (Taxol), PTX) is a promising anti-cancer drug and has been successfully used to treat a wide variety of cancers. Unfortunately, serious clinical side effects are associated with it, which are caused by PTX itself and non-aqueous vehicle containing Cremophor EL. Development of new formulation of PTX with better efficacy and fewer side effects is extremely urgent. In the present study, a N-octyl-O-sulfate chitosan (NOSC) micelle was developed and used as the delivery system for PTX. The pharmacokinetics, biodistribution, efficacy and safety of PTX-loaded NOSC micelles (PTX-M) were evaluated. The results showed that NOSC micelles had high drug loading capacity (69.9%) and entrapment efficiency (97.26%). The plasma AUC of PTX-M was 3.6-fold lower than that of Taxol; but the V(d) and CL of PTX-M were increased by 5.7 and 3.5-fold, respectively. Biodistribution study indicated that most of the PTX were distributed in liver, kidney, spleen, and lung and the longest retention effect was observed in the lung. Drug safety assessment studies including acute toxicity, hemolysis test, intravenous stimulation and injection anaphylaxis revealed that the PTX-M was safe for intravenous injection. Furthermore, the comparable antitumor efficacy of PTX-M and Taxol was observed at the same dose of 10 mg/kg in in vivo antitumor mice models inoculated with sarcoma180, enrich solid carcinoma (EC), hepatoma solidity (Heps), Lewis lung cancer cells and A-549 human lung cancer cells. These results clearly showed that PTX-M had the similar antitumor efficacy as Taxol, but significantly reduced the toxicity and improved the bioavailability of PTX.
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PMID:Pharmacokinetics, biodistribution, efficacy and safety of N-octyl-O-sulfate chitosan micelles loaded with paclitaxel. 1809 46

Solvent-based delivery vehicles for chemotherapy agents have been instrumental in providing a means for hydrophobic agents to be administered intravenously. These solvents, however, have been associated with serious and dose-limiting toxicities. Solvent-based formulations of taxanes, a highly active class of cytotoxic agents, are associated with hypersensitivity reactions, neutropenia, and neuropathy. Nanoparticle technology utilizing the human protein albumin exploits natural pathways to selectively deliver larger amounts of drug to tumors while avoiding some of the toxicities of solvent-based formulations. 130 nM albumin-bound (nab) paclitaxel (nab-paclitaxel; Abraxane) was recently approved for use in patients with metastatic breast cancer who have failed combination therapy. In a randomized, phase III study in metastatic breast cancer, nab-paclitaxel was found to have improved efficacy and safety compared with conventional, solvent-based paclitaxel. Preliminary data also suggest roles for nab-paclitaxel as a single agent and in combination therapy for first-line treatment of metastatic breast cancer as well as in other solid tumors, including non-small-cell lung cancer, ovarian cancer, and malignant melanoma. The nab technology promises to have broad utility in cancer therapy, and clinical trials are underway using nab formulations of other water-insoluble anticancer agents such as docetaxel and rapamycin.
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PMID:Protein nanoparticles as drug carriers in clinical medicine. 1842 79


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