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)

Gemcitabine, a nucleoside analogue for treating lung cancer, is clinically administered as an intravenous infusion. To achieve better patient compliance and more direct effect on the lung, we explored a new gemcitabine pulmonary delivery route and evaluated the pharmacokinetics and acute lung injury aspects in animals. Pharmacokinetics of gemcitabine were measured in Sprague-Dawley rats after intravenous (i.v.), intratracheal instillation by tracheotomy (i.t.t.), intratracheal instillation via orotrachea (i.t.o.), and intragastric (i.g.) administration of gemcitabine. Acute lung injury effects of the pulmonary delivery of gemcitabine were performed in Sprague-Dawley rats after i.t.o. and i.v. administration of gemcitabine and i.t.o. administration of lipopolysaccharide (LPS) as a positive control and physiological saline as a blank control. Indicators for acute lung injury that were evaluated included lung morphology, lung histopathology, lung coefficient, lung wet/dry weight ratio, total cell and classification counts in bronchoalveolar lavage cells (BALC), and total protein and TNF-alpha levels in bronchoalveolar lavage fluids (BALF). After i.t.t. or i.t.o. administration, gemcitabine was quickly absorbed, but i.g. administration led to an undetectable plasma gemcitabine concentration. Absolute bioavailability of gemcitabine after i.t.t. and i.t.o. administration was 91% and 65%, respectively. Gemcitabine given as i.t.o. administration did not cause any overt acute lung injury. All indicators for acute lung injury in the i.t.o. group were similar to those in the i.v. group or in the blank control, but significantly different from those in the positive control. In conclusion, the pharmacokinetics and acute lung injury studies suggest that pulmonary gemcitabine delivery would be a new and promising administration route.
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PMID:Pulmonary gemcitabine delivery for treating lung cancer: pharmacokinetics and acute lung injury aspects in animals. 1843 90

Concurrent chemoradiotherapy (CCR) followed or preceded by full-dose chemotherapy seems to be a standard treatment for unresectable non-small cell lung cancer (NSCLC). Gemcitabine is a strong radiosensitizer, and a phase I study confirmed the feasibility of CCR with low-dose gemcitabine administered twice-weekly in NSCLC patients. Consequently, we designed a prospective, multicentric, phase II trial to evaluate the efficacy and toxicity of this approach, following induction chemotherapy with cisplatin and gemcitabine. We included patients with unresectable stage III NSCLC, no pleural effusion, adequate pulmonary, renal, liver and hematological functions, Karnofsky index >70 and planned treated volume (PTV) <2200cm3. Treatment consisted of 3 cycles of cisplatin (100mg/m2, d1) and gemcitabine (1250mg/m2, d1 and 8) q3w, followed by CCR (gemcitabine 50mg/m2 on Mondays and Thursdays and radiotherapy 68.4Gy, 1.8Gyqd). After the inclusion of 22 patients (group A), an unacceptable toxicity was detected. Thus, cisplatin dose was reduced to 70mg/m2, and gemcitabine dose was adjusted to 35mg/m2 during CCR. Another 34 patients (33 eligible, group B) were included. Five patients in group A and 6 patients in group B discontinued the study treatment during induction. Thus, 17 and 27 patients, respectively initiated CCR. Hematological toxicity (grades III and IV) was particularly relevant in group A during this phase, with 35 and 23% of thrombopenia and neutropenia, respectively. Nonhematological grades III-IV toxicity of chemoradiation was significant and similar in groups A and B: esophagitis 35.2 and 33.3% and pneumonitis 23.5 and 25.9%, respectively. 40.9% of patients in group A vs. 57.5% in group B completed treatment. Overall response (intention-to-treat analysis) was 68.1% in group A and 63.5% in group B. Median survival was 17.7 months for the whole group with a mean follow-up of 41.2 months. 20% of patients were alive at 3 years. Long-term results of this schedule are encouraging. However, nonhematological toxicity of chemoradiation is substantial and different strategies should be tested to minimize it.
Lung Cancer 2008 Oct
PMID:Induction chemotherapy with cisplatin and gemcitabine followed by concurrent chemoradiation with twice-weekly gemcitabine in unresectable stage III non-small cell lung cancer: final results of a phase II study. 1844 89

PNAS-4 has been demonstrated to induce apoptosis in U2OS cells. To evaluate its feasibility as a new strategy for cancer therapy, we analyzed its anti-tumor effect with or without gemcitabine in A549 lung cancer cells. MTT assay, Hoechst 33258 staining and flow cytometric analysis were used to determine the cytotoxicity of PNAS-4 alone or plus gemcitabine. The anti-tumor efficacy was further investigated in vivo with nude mice. PNAS-4 plasmid/liposome complexes were injected by tail vein every 4 days. Gemcitabine was given ip on a weekly schedule for 4 weeks. PNAS-4 alone and plus gemcitabine induced apoptosis in A549 cells in vitro. The xenograft lung cancer treated with PNAS-4 retarded growth compared with the empty vector. The combination of PNAS-4 with gemcitabine induced anti-tumor activity accompanied by an increase in apoptotic cells compared with PNAS-4 or gemcitabine alone. No other obvious toxicity was found. PNAS-4 therefore suppresses tumor growth in vivo and enhances sensitivity to gemcitabine. This suggests that the PNAS-4 gene could be a potential candidate for lung cancer therapy alone or in combination with gemcitabine.
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PMID:Genetic transfer of PNAS-4 induces apoptosis and enhances sensitivity to gemcitabine in lung cancer. 1910 42

Pemetrexed is a multitargeted antifolate that inhibits at least three folate dependent enzymes involved in DNA synthesis. Gemcitabine is a broadly active pyrimidine nucleoside antimetabolite that is incorporated into DNA and causes chain termination. Both pemetrexed and gemcitabine, as single agents, have shown antitumor activity in a wide range of solid tumors, including non-small-cell lung cancer (NSCLC). Based on preclinical in vitro and in vivo synergism of the combination of pemetrexed and gemcitabine, the 2 drugs were studied in several phase I and II trials in patients with advanced NSCLC. The published studies found response rates between 13 to 31%, with overall survival times similar to established standard chemotherapy regimens. The grade 3 or 4 toxicities with this combination are mainly haematologic, dermatologic and transaminitis. In this paper, we review the pemetrexed-gemcitabine combination in the treatment of NSCLC patients with regards to the rationale, clinical activity as well as the future directions for this new 2-drug combination.
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PMID:The role of pemetrexed combined with gemcitabine for non-small-cell lung cancer. 1983 26

Gemcitabine (Gemzar) is a nucleoside analogue used as a cytotoxic agent for the treatment of various carcinomas: pancreatic cancer, bladder cancer, breast cancer, and non-small-cell-lung cancer. Carboplatin, a DNA alkylating agent, is used alongside with gemcitabine in a regimen known as GemCarbo chemotherapy to treat several different types of cancer, most commonly lung cancer. We report an unusual case of hand-foot hyperpigmentation after the use of GemCarbo therapy on a man with stage IV non-small cell lung carcinoma. Physical examination revealed hyperpigmented lesions that were approximately 1-2 mm in diameter, of brown/purple discoloration localized to the palmar surface of his hands and the dorsum of his feet. A rapid plasma reagin blood test, used for the screening of syphilis was nonreactive. Discontinuation of both agents resulted in the dramatic disappearance of the lesions over the course of 2 weeks. In this report, we describe, to our knowledge, the first case of hand-foot hyperpigmentation that has been reported with the use of either of these 2 agents.
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PMID:Hand-foot hyperpigmentation skin lesions associated with combination gemcitabine-carboplatin (GemCarbo) therapy. 2046 Sep 84

Gemcitabine is a novel pyrimidine nucleoside antimetabolite agent that is active, either as monotherapy or in association with other cytotoxic compounds, in pancreatic, ovarian, breast, bladder and non-small-cell lung cancer. The drug has an acceptable toxicity profile with myelosuppression being the most common adverse event. Pharmacoeconomic assessments have been performed in order to determine whether gemcitabine is a cost effective cancer treatment. Several cost analyses have investigated gemcitabine in association with cisplatin in the treatment of non-small-cell lung cancer, indicating that the combination is cost effective when compared with either old- or new-generation platinum-based treatments. Results in other malignancies are not corroborated by the same quality of evidence, therefore more extensive analyses are warranted. Overall, available data indicate that accurate selection of patients and careful cost analyses should be included in the development of new anticancer drugs for an appropriate use of limited healthcare resources.
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PMID:Is gemcitabine cost effective in cancer treatment? 2052 11

Cell-monolayer-based assays for chemotherapeutic drug discovery have proven to be highly artificial compared with physiological systems. The objective of this study was to culture cancer cells in a simple 3-dimensional (3D) collagen gel model to study the antiproliferative activity of known lung cancer drugs. The validity of our 3D model was tested by measuring the activity of 10 lung cancer drugs (Paclitaxel, Alimta, Zactima, Doxorubicin, Vinorelbine, Gemcitabine, 17AAg, Cisplatin, and 2 experimental drugs from the University of Kansas [KU174 and KU363]) in 2 lung cancer cell lines (A549 and H358) and comparing the activity in a traditional 2-dimensional (2D) in vitro cellular assay. Both potency and efficacy of these drugs were calculated to evaluate the activity of the drugs. Our results demonstrate that the activity of these drugs showed significant differences when tested in 3D cultures, which varied with individual drugs and the cell line used for testing. For example, the cytotoxicity of Paclitaxel, KU174, Alimta, Zacitma, Doxorubicin, Vinorelbine, KU363, and 17AAg was significantly changed when tested in the 3D model, whereas the potency of Cisplatin and Gemcitabine in H358 cell line remained unaffected. A similar pattern, with some differences, was observed in A549 cells and is discussed in detail in this article. The observed differences in potency and efficacy of the cancer drugs in 3D models suggest that the biological implications of screening configurations should be taken into account to select superior cancer drug candidates in preclinical studies.
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PMID:Activity of anticancer agents in a three-dimensional cell culture model. 2066 35

The most widely used approach to cancer immunotherapy is vaccines. Unfortunately, the need for multiple administrations of antigens often limits the use of one of the most effective vaccine approaches, immunogene therapy using viral vectors, because neutralizing antibodies are rapidly produced. We hypothesized that after viral immunogene therapy "primed" an initial strong antitumor immune response, subsequent "boosts" could be provided by sequential courses of chemotherapy. Three adenoviral (Ad)-based immunogene therapy regimens were administered to animals with large malignant mesothelioma and lung cancer tumors followed by three weekly administrations of a drug regimen commonly used to treat these tumors (Cisplatin/Gemcitabine). Immunogene therapy followed by chemotherapy resulted in markedly increased antitumor efficacy associated with increased numbers of antigen-specific, activated CD8(+) T-cells systemically and within the tumors. Possible mechanisms included: (i) decreases in immunosuppressive cells such as myeloid-derived suppressor cells (MDSC), T-regulatory cells (T-regs), and B-cells, (ii) stimulation of memory cells by intratumoral antigen release leading to efficient cross-priming, (iii) alteration of the tumor microenvironment with production of "danger signals" and immunostimulatory cytokines, and (iv) augmented trafficking of T-cells into the tumors. This approach is currently being tested in a clinical trial and could be applied to other trials of viral immunogene therapy.
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PMID:Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. 2068 43

Gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analog, and erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, are used clinically to treat patients with non-small-cell lung cancer (NSCLC). However, the molecular mechanisms for the drug resistance of gemcitabine in NSCLC cells are poorly understood. In this study, we used constructs containing human Rad51 cDNA or specific Rad51 small interfering RNA (siRNA) to examine the role of Rad51 in chemoresistance of gemcitabine in three different human NSCLC cell lines. Exposure of human NSCLC cell lines to gemcitabine increased the phosphorylation levels of mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 and AKT in a time- and dose-dependent manner, which was accompanied by an induction of Rad51 mRNA and protein expression. Gemcitabine increased the expression of Rad51 by increasing its mRNA and protein stability. Blockage of ERK1/2 or AKT activation by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126; MKK1/2 inhibitor) or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002; phosphatidyl inositol 3-kinase inhibitor), respectively, decreased the gemcitabine-induced Rad51 expression. Gemcitabine-induced cytotoxicity was significantly increased using siRNA depletion of Rad51 or blockage of ERK1/2 and AKT activation. Erlotinib enhanced the gemcitabine-induced cytotoxicity via the inactivation of ERK1/2 and AKT and the down-regulation of Rad51. Enforced expression of constitutively active MKK1/2 or AKT recovered cell viability and Rad51 protein levels that were decreased by the combination of erlotinib and gemcitabine. Suppression of Rad51 expression or the inactivation of ERK1/2 or AKT signaling may be considered potential therapeutic modalities for gemcitabine-resistant lung cancer.
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PMID:Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human non-small-cell lung cancer cells. 2085 43

Gemcitabine in combination with the oral epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, is a treatment option for patients with advanced pancreatic cancer. Lung toxicity has been described for each of these drugs. A 59-year-old man with advanced non-small-cell lung cancer developed acute respiratory failure with bilateral interstitial lung disease 4 weeks after the onset of second-line combination therapy that included gemcitabine and erlotinib. Despite discontinuation of gemcitabine and erlotinib, treatment with corticosteroids was ineffective and the patient gradually deteriorated and died with progressive respiratory failure 2 months after the start of the gemcitabine/erlotinib combination. It was concluded that a synergistic effect between gemcitabine and erlotinib could have been responsible for this fatal pulmonary toxicity. Physicians should be aware of the potential severe lung toxicity of this combination. The potential role of corticosteroids in the management of this toxicity is unknown.
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PMID:Fatal interstitial lung disease associated with gemcitabine and erlotinib therapy for lung cancer. 2126 48


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