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 is a pyrimidine analog of deoxycytidine with activity against nonhematologic and hematologic malignancies. Its pulmonary toxicity is usually mild and self-limiting. We describe a male patient with lung cancer in whom severe dyspnea and interstitial infiltrates developed after the administration of gemcitabine.
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PMID:Severe pulmonary toxicity in a patient treated with gemcitabine. 1182 91

Gemcitabine (2'-2'-difluorodeoxycytidine) is a recently developed pyrimidine antagonist that is structurally related to cytarabine (ara-C). When phosphorylated intracellularly, gemcitabine inhibits ribonucleotide reductase and arrests cell cycling in the S phase. Paclitaxel is a potent promoter and stabilizer of microtubule spindle formation and an inhibitor of cell cycling. In this report, we discuss 2 patients with advanced-stage non-small-cell lung cancer (NSCLC) treated with a combination of gemcitabine/paclitaxel who developed pulmonary symptoms of dyspnea and cough. Chest radiographs and computed tomography revealed diffuse pulmonary infiltrates. Bronchoscopic evaluation revealed diffuse alveolar damage with associated type II pneumocyte hyperplasia without evidence of infection or metastatic carcinoma, suggesting the development of a drug-induced pulmonary toxicity. Both cases improved with the discontinuation of gemcitabine/paclitaxel and with supportive care including steroids in one of the patients. We also review the published case reports of pneumonitis believed to be secondary to the taxanes or gemcitabine when used as single agents and a solitary case report describing pneumonitis in the setting of both a taxane and gemcitabine. Because the combination of gemcitabine/paclitaxel has demonstrated activity in NSCLC, the use of this combination is likely to increase. Clinicians caring for lung cancer patients receiving this combination should be aware of this potential pulmonary toxicity.
Clin Lung Cancer 2002 Jul
PMID:Hypersensitivity pneumonitis in advanced non-small-cell lung cancer patients receiving gemcitabine and paclitaxel: report of two cases and a review of the literature. 1465 77

Small-cell lung cancer (SCLC) accounts for 20%-25% of all new cases of lung cancer and represents the sixth most commonly diagnosed cancer in the United States. Given the tumor's systemic nature and chemoresponsiveness, chemotherapy has become the cornerstone of its management. Chemotherapy significantly prolongs survival; however, most of the patients still die within 2 years of diagnosis. Combination chemotherapy represents the treatment of choice for this disease. In the United States, cisplatin/etoposide is the regimen most frequently used for the first-line therapy of SCLC patients because of its better therapeutic index. Upon recurrence, topotecan is the Food and Drug Administration-approved treatment based on a phase III trial that showed no statistically significant differences in survival or response for topotecan compared with CAV (cyclophosphamide/doxorubicin/vincristine) but a better disease-related symptom improvement compared to baseline favoring the topoisomerase I inhibitor. Newer agents, with novel mechanisms of action, have shown activity against SCLC and are being tested in many different combinations. Among these agents, gemcitabine has attractive mechanisms of action and toxicity profile. Gemcitabine is a pyrimidine nucleoside antimetabolite, analogue to cytosine arabinoside, which through incorporation into the DNA leads to inhibition of DNA synthesis and cytotoxicity. As a single agent, gemcitabine has modest activity against SCLC. However, like with many other drugs, response rates improve when gemcitabine is used in combination regimens. Phase II and III studies of combinations with classic drugs for the management of SCLC patients such as cisplatin and/or etoposide and gemcitabine demonstrate comparable results to those of standard therapies. The gemcitabine/paclitaxel and gemcitabine/topoisomerase I inhibitor combinations are also of great interest, and preliminary results in previously treated patients are promising. The proper role of gemcitabine in the treatment of patients with SCLC awaits future testing in randomized phase III trials.
Clin Lung Cancer 2003 Jan
PMID:New agents in the treatment of small-cell lung cancer: focus on gemcitabine. 1472 Mar 38

Pemetrexed (Alimta ) is a novel multitargeted antifolate that inhibits 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent has broad antitumor activity in phase II trials in a wide variety of solid tumors. In non-small-cell lung cancer (NSCLC), single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine. A pivotal phase III study in mesothelioma has been presented, indicating the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. Approval for pemetrexed in combination with cisplatin in advanced mesothelioma is expected within the next 12 months. This review discusses the activity of pemetrexed in NSCLC.
Clin Lung Cancer 2003 Jan
PMID:Current data with pemetrexed (Alimta) in non-small-cell lung cancer. 1472 Mar 39

Research aimed at identifying effective chemopreventive compounds active against carcinogenesis of the upper respiratory tract (URT) has been largely unsuccessful. We are addressing this problem by efforts at agent identification and by using aerosol delivery. Two compounds, difluoromethylornithine (DFMO) and 5-fluorouracil (5-FU) were investigated. DFMO is an irreversible inhibitor of ornithine decarboxylase, an enzyme important in cell proliferation. It has been used widely by oral administration for chemoprevention. 5-FU is a pyrimidine analog used extensively as a chemotherapeutic agent. It is generally administered i.v. and can cause considerable toxicity. However, aerosol administration for therapy of lung cancer in humans has been reported to be without adverse effects (Tatsumura et al., Br J Cancer 1993;68:1146-9). The experimental model used herein entailed six intratracheal administrations of methylnitrosourea (MNU) to hamsters. Each of the test agents was started about 1 week after MNU and was continued for 29 weeks with DFMO. Infiltrating squamous cell carcinomas of the URT occurred in 92% of the controls and were reduced by 50% in animals receiving DFMO (P = 0.0001). The experiment with 5-FU was of shorter duration being terminated 20 weeks after MNU. Thirty percent of the controls had infiltrating carcinomas and were reduced by 60% in animals receiving 5-FU (P = 0.0274). Both compounds resulted in a significant increase in the percent of cancer-free animals. These two agents may have selected use in subjects at high risk of cancer of the URT.
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PMID:Chemoprevention of cancer of the upper respiratory tract of the Syrian golden hamster by aerosol administration of difluoromethylornithine and 5-fluorouracil. 1505 84

Pemetrexed is a novel multitargeted antifolate that inhibits > or = 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent has broad antitumor activity in phase II trials in a wide variety of solid tumors, and is approved in combination with cisplatin for the therapy of malignant mesothelioma. In a recent phase III trial, pemetrexed demonstrated equivalent efficacy to docetaxel, but with significantly less toxicity, in second-line treatment of non-small-cell lung cancer. The most common and serious toxicities of pemetrexed--myelosuppression and mucositis--have been significantly ameliorated by folic acid and vitamin B12 supplementation. More important, vitamin supplementation has not been shown to adversely affect efficacy in some tumor types. Tumors with codeletion of the methylthioadenosine phosphorylase gene, as a consequence of p16 deletions, may be particularly sensitive to pemetrexed. In this review, the biochemistry and mechanism of action of pemetrexed are discussed.
Clin Lung Cancer 2004 Apr
PMID:Pharmacology and mechanism of action of pemetrexed. 1511 25

The treatment of advanced non-small-cell lung cancer (NSCLC) has evolved rapidly over the past few years. Systemic chemotherapy is associated with both quality of life and modest survival benefit for patients with advanced NSCLC. Platinum-based doublet combinations are the "standard of care." The US Food and Drug Administration (FDA) has approved gemcitabine (Gemzar), a pyrimidine analog, to be used in combination with cisplatin for the treatment of advanced NSCLC in the first-line setting. Randomized clinical trials have established comparable efficacy with improved therapeutic index for the carboplatin/gemcitabine regimen when compared with cisplatin/gemcitabine and other platinum doublets. Nonhematologic toxicities occur at a lower frequency with carboplatin/gemcitabine combinations compared with other "standard" platinum-based doublets, whereas dose-limiting thrombocytopenia, the most common toxicity, rarely requires therapeutic intervention. Both the 3- and 4-week schedules of carboplatin/gemcitabine result in similar efficacy and toxicity profiles, but the 3-week regimen is preferred. The combination of carboplatin and gemcitabine is an effective regimen with an acceptable toxicity profile for the treatment of advanced NSCLC. This regimen can also be used as a foundation for the development of innovative combinations with molecularly targeted agents.
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PMID:Carboplatin/gemcitabine combination in advanced NSCLC. 1533 55

Purine bases and their bioisosteric analogs are widely used as building blocks in combinatorial chemistry. Recently a great number of fused pyrimidine derivatives became known as potential drug molecules against various types of proliferative diseases, caused by over-expression of protein kinases. One of the most important compound families are quinazolines : e.g. the best inhibitor of EGFR tyrosine kinase is PD153035 (6,7-dimethoxy-4-(3'-bromophenyl)amino-quinazoline) and IRESSA (gefitinib, ZD1839), developed from this compound family, is presently the only one approved and granted drug by the FDA for the treatment of advanced non-small-cell lung cancer (NSCLC). KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]-quinazoline-2-thione dihydrochloride) from this group, showed significantly higher inhibitory activity on cyclic GMP-specific phosphodiesterase compared with those of sildenafil (Viagra). The synthetic procedures of the example compounds are based on imidoyl chloride intermediates that were prepared from the appropriate 3H-quinazoline-4-ones. Although the key intermediates, quinazoline-4-ones, have been known since more than hundred years, their synthetic procedures have been improved much only in the past ten years. In this paper we reviewed the efficient synthetic methods of quinazolin-4-ones, and presented a novel, reliable method for their synthesis. There was no considerable effect of microwave-, or traditional thermal activation on the yield and compound purity.
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PMID:Improved, high yield synthesis of 3H-quinazolin-4-ones, the key intermediates of recently developed drugs. 1554 62

The pyrimidine analogue gemcitabine is an established effective agent in the treatment of non-small-cell lung cancer (NSCLC). The present study investigates whether gemcitabine would be synergistic with the topoisomerase I inhibitor topotecan against the NSCLC A549 and Calu-6 cells. Cells were treated with gemcitabine and topotecan for 1 h and the type of drug interaction was assessed using the combination index (CI). Cell cycle alterations were analysed by flow cytometry, while apoptosis was examined by the occurrence of DNA internucleosomal fragmentation, nuclear condensation and caspase-3 activation. Moreover, the possible involvement of the PI3K-Akt signalling pathway was investigated by the measurement of Akt phosphorylation. Finally, quantitative, real-time PCR (QRT-PCR) was used to study modulation of the gemcitabine-activating enzyme deoxycytidine kinase (dCK) and the cellular target enzyme ribonucleotide reductase (RR). In results, it was found that simultaneous and sequential topotecan --> gemcitabine treatments were synergistic, while the reverse sequence was antagonistic in both cell lines. DNA fragmentation, nuclear condensation and enhanced caspase-3 activity demonstrated that the drug combination markedly increased apoptosis in comparison with either single agent, while cell cycle analysis showed that topotecan increased cells in S phase. Furthermore, topotecan treatment significantly decreased the amount of the activated form of Akt, and enhanced the expression of dCK (+155.0 and +115.3% in A549 and Calu-6 cells, respectively), potentially facilitating gemcitabine activity. In conclusion, these results indicate that the combination of gemcitabine and topotecan displays schedule-dependent activity in vitro against NSCLC cells. The gemcitabine --> topotecan sequence is antagonistic while drug synergism is obtained with the simultaneous and the sequential topotecan --> gemcitabine combinations, which are associated with induction of decreased Akt phosphorylation and increased dCK expression.
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PMID:Interaction between gemcitabine and topotecan in human non-small-cell lung cancer cells: effects on cell survival, cell cycle and pharmacogenetic profile. 1570 43

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient (folate and vitamin B 12 ) patients, and can be ameliorated by the co-administration of folate and vitamin B 12 . The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non-small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of single-agent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted.
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PMID:The evolving role of pemetrexed (Alimta) in lung cancer. 1581 33


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