Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Concurrent radiochemotherapy (RCT) is a promising new therapy option in advanced non-small cell lung cancer (NSCLC). In randomized trials concomitant RCT has been shown to be superior compared to radiotherapy alone and to sequential radiochemotherapy. In most treatment schedules platinum salts alone or in combination with etoposide, mitomycin C or vinca-alkaloids have been used. Up to now altered fractionation schemas-particularly hyperfractionated radiotherapy-have not been demonstrated to be superior to conventional fractionation (2 Gy daily up to 56-60 Gy), when employed concurrently to chemotherapy. Nevertheless open questions remain: (1) What is the best chemotherapy administered simultaneously to radiotherapy? (2) Might newer drugs (e.g. taxanes, inhibitors of topoisomerase I and II, gemcitabine) be more effective and reveal fewer side effects compared to platinum salts? (3) Is there a role for adjuvant chemotherapy following RCT? (4) What is the most effective radiotherapy schedule in concepts with RCT? (5) What radiation dose is necessary to optimize local control in RCT?
Lung Cancer 2001 Sep
PMID:Concomitant radiochemotherapy of advanced non-small-cell lung cancer. 1157 10

In the last years, the main topoisomerase I inhibitors (TP1-I) (i.e. topotecan and irinotecan) have been used in combination chemotherapy in non-small cell lung cancer. Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen.
Lung Cancer 2001 Dec
PMID:Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer. 1174 1

A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.
 ...
PMID:Novel angular benzophenazines: dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents. 1180 24

Reverse transcription polymerase chain reaction (RT-PCR) single-strand conformation polymorphism analysis was used to detect topoisomerase I (top1) mutations in total RNA from 16 specimens that were excised during surgery from eight patients with non-small cell lung cancer (NSCLC) who had received preoperative chemotherapy consisting of irinotecan (CPT-11) and cisplatin. PCR single-strand conformation polymorphism and subsequent DNA sequencing analysis showed two nucleotide substitutions resulting in Trp736stop (TGG to TGA) and Gly737Ser (GGT to AGT) in one tumor specimen. The mutations were located near a site in top1 that was previously reported to harbor a mutation in the human lung cancer cell line PC7/CPT, which was selected for CPT resistance. These results demonstrate that mutations in top1 occur after chemotherapy with CPT-11 in NSCLC patients and suggest that development of resistance to CPT-11 in some patients may involve mutation of top1. However, the significance of top1 mutations to CPT resistance needs to be further investigated.
Lung Cancer 2002 Mar
PMID:Point mutations in the topoisomerase I gene in patients with non-small cell lung cancer treated with irinotecan. 1184 5

Based on the synergistic cytotoxicity demonstrated in vitro by topoisomerase I inhibitors followed by docetaxel and the feasibility of giving both drugs on a weekly schedule avoiding overlapping toxicities, we designed a phase I trial of weekly CPT-11 (irinotecan)/docetaxel to determine the dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) of this combination. Eighteen patients with advanced solid tumors treated with at least one prior chemotherapy regimen were included in this trial. CPT-11 was administered as a 90-min (intravenous) IV infusion followed immediately by docetaxel as a 30-min IV infusion. Both drugs were given on days 1, 8 and 15 in 4-week cycles. Four escalating dose levels of CPT-11/docetaxel (level I: 60/20 mg/m(2), level II: 60/25 mg/m(2), level III: 70/25 mg/m(2), and level IV: 70/30 mg/m(2)) were studied. Forty-seven cycles were administered (range, 1-5 courses) with a median number of 2.6 cycles per patient. Grade 4 leukopenia was the DLT reached at dose-level IV (CPT-11/docetaxel 70/30 mg/m(2)). Four patients had grade 3 anemia at dose levels III (two patients) and IV (two patients), while grade 3/4 thrombocytopenia was not seen. Grade 3/4 non-hematologic toxicities included grade 3 diarrhea in two patients (dose levels II and IV), grade 3 asthenia in one patient (dose level II) and grade 3 stomatitis in one patient (dose level I). The recommended dose of this weekly schedule is CPT-11 70 mg/m(2) and docetaxel 25 mg/m(2). DLT of this regimen is leukopenia, although toxicity is manageable at the recommended dose level. The activity of this regimen is being evaluated in a phase II study in previously treated patients with advanced non-small cell lung cancer.
Lung Cancer 2002 Aug
PMID:Phase I study of weekly CPT-11 (irinotecan)/docetaxel in patients with advanced solid tumors. 1214 Jan 45

A novel anti-tumor agent, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103), effectively inhibits both topoisomerase I and II activities. To enhance anti-tumor efficacy and to reduce the side effects of the agent, liposomalization of TAS-103 was performed. TAS-103 was effectively entrapped in liposomes by a remote-loading method, and was stable at 4 degrees C and in the presence of 50% serum. To evaluate the anti-tumor efficacy of liposomal TAS-103, the growth inhibition against Lewis lung carcinoma cells in vitro and the therapeutic efficacy against solid tumor-bearing mice in vivo were examined. Liposomal TAS-103 showed strong cytotoxic effect against Lewis lung carcinoma cells in a dose dependent manner and effectively suppressed solid tumor growth accompanying longer survival time of tumor-bearing mice in comparison with the mice treated with free TAS-103. These results suggest that liposomal TAS-103 is useful for cancer therapy.
 ...
PMID:Cancer chemotherapy by liposomal 6-[12-(dimethylamino)ethyl]aminol-3-hydroxy-7H-indeno[2,1-clquinolin-7-one dihydrochloride (TAS-103), a novel anti-cancer agent. 1239 2

Rebeccamycin analogues containing one azaindole unit, with and without a methyl group on the imide nitrogen and with the sugar moiety coupled either to the indole nitrogen or to the azaindole nitrogen were synthesized. To increase the solubility and induce stronger interactions with the target macromolecules, a bromo or nitro substitutent was introduced on the indole unit. The DNA binding and topoisomerase I inhibition properties were investigated together with the antiproliferative activities toward nine tumor cell lines. In addition, the effect of the compounds on the cell cycle of L1210 leukemia cells was examined. The nonaza analogues were found to be cytotoxic against all cell lines of the panel whereas the aza-analogues showed a selective action toward certain cell lines. They strongly inhibited the proliferation of SK-N-MC neuroblastoma, A431 epidermoid carcinoma and NCI-H69 small cell lung carcinoma cells, but showed little or no cytotoxic effect against IGROV ovary carcinoma, HT29 colon carcinoma, and A549 non small cell lung carcinoma cells. Whatever their cytotoxicity profile, all compounds induce similar cell cycle effects, with a marked G2+M block observed with L1210 leukemia cells. The data suggest that the molecular mechanism of action of the aza-analogue derivatives is different from that of rebeccamycin.
 ...
PMID:Syntheses and antiproliferative activities of 7-azarebeccamycin analogues bearing one 7-azaindole moiety. 1257 Mar 82

Despite the high response rates to chemotherapy, small-cell lung cancer (SCLC) is among the most lethal malignancies. Long-term survival is anecdotal for patients with extensive disease; 5-years survival is < or =5% for those with limited disease. All patients with extensive disease and most patients with limited disease will experience disease progression and become candidates for second-line therapy. Although a number of agents have demonstrated antitumor activity in relapsed SCLC, including paclitaxel, docetaxel, etoposide, cisplatin, and carboplatin, topotecan is the only single agent currently approved in the United States for the treatment of recurrent disease. Topotecan is a novel topoisomerase I inhibitor with established antitumor activity in recurrent SCLC and has a predictable, noncumulative toxicity profile. Furthermore, topotecan has been shown to provide symptom improvement in this predominantly palliative setting. Evidence also suggests that topotecan readily penetrates the blood-brain barrier and might be active in the relatively large subset of SCLC patients who experience brain metastases. This article reviews the clinical utility of topotecan in recurrent SCLC, including its efficacy, tolerability, and quality-of-life effect, when used as monotherapy and in novel combination regimens.
Lung Cancer 2003 Jun
PMID:Treatment of relapsed small-cell lung cancer--a focus on the evolving role of topotecan. 1278 21

Topotecan, a novel topoisomerase I inhibitor, is an established treatment for patients with recurrent small-cell lung cancer (SCLC), with antitumor response rates of approximately 20% and median survival of approximately 32 weeks in patients with extensive-stage disease. Topotecan's comparable activity relative to other agents used in SCLC and its novel mechanism of action, noncumulative toxicity, and in vitro synergy with other active agents have provided the rationale for investigating topotecan in first-line therapy. Furthermore, topotecan penetrates the blood-brain barrier and is potentially useful for the relatively large subset of patients with SCLC and brain metastases. In early studies of topotecan in brain metastases, encouraging antitumor activity has been observed. In several feasibility and phase II studies of topotecan as single-agent therapy in patients with extensive- and limited-stage tumors and as part of novel first-line combination regimens, overall response rates have ranged from 42% to 100%. Complete responses of 3%-67% and partial responses of 33%-80% have been observed in first-line therapy. Furthermore, the median overall survival in patients receiving topotecan in first-line therapy has ranged from approximately 8 months (extensive-stage disease) to 20 months (limited-stage disease). The most frequent adverse events associated with topotecan-based regimens include grade 3/4 neutropenia and thrombocytopenia that often require the incorporation of growth factor support into the treatment regimen. Nonhematologic adverse events associated with topotecan-based combination regimens have been mild or primarily attributed to other agents in the combination. Alternative doses and schedules (3 consecutive days and weekly) are being explored because they appear to be associated with considerably less myelosuppression. Although several trials have established the feasibility and activity of topotecan in first-line therapy of patients with SCLC, randomized phase III studies with comparison to standard therapy will be required to confirm a potential role for this active agent and to determine the optimal dosing regimen.
Clin Lung Cancer 2003 Mar
PMID:Emerging role of topotecan in first-line therapy of small-cell lung cancer. 1460 45

More than one third of all non-small-cell lung cancer (NSCLC) patients present with advanced stage IV disease with metastases or with stage IIIB disease with a malignant pleural or pericardial effusion. The prognosis for these patients remains poor despite some improvement in survival produced by 2-drug chemotherapy combinations. With the best 2-drug combinations, the expected median survival is 8-9 months and > 80% of patients die within 2 years of diagnosis. The overall response rate to the best combination is < 40% and the complete response rate is only 1%. Clearly, superior therapies are needed. The topoisomerase I inhibitors have been developed because the topoisomerase I enzyme plays a critical role in the DNA repair process. Irinotecan is a topoisomerase I inhibitor developed during the 1990s. It was initially approved in the United States for the treatment of colorectal cancer. In early trials, considerable activity was seen in both small-cell lung cancer and NSCLC. These observations led to combination studies with cisplatin. Cisplatin-based therapy had become a standard approach in both stage IV disease and in combination with chest radiotherapy in stage IIIB disease because metaanalyses of randomized trials showed that cisplatin-based therapy significantly improved survival. Randomized trials also showed that cisplatin-based therapy improved symptoms in the majority of patients and improved quality of life. In early combination studies, the irinotecan/cisplatin combination produced responses in an average of 40% of patients and produced median survival times that averaged about 10 months. In randomized trials comparing irinotecan/cisplatin to vindesine/cisplatin, the irinotecan/cisplatin combination was slightly better than irinotecan alone and vindesine/cisplatin. These encouraging results led to ongoing randomized trials comparing the 2-drug combination of irinotecan/cisplatin to other 2-drug combinations. Irinotecan has also been combined safely and effectively with carboplatin. The 2-drug combination of irinotecan/carboplatin produced results similar to those achieved with irinotecan/cisplatin. Irinotecan has also been incorporated into 3-drug combinations such as irinotecan/carboplatin/paclitaxel with encouraging results. A randomized trial comparing docetaxel/irinotecan to docetaxel/cisplatin showed similar results. Randomized trials comparing the 3-drug combination to a 2-drug combination are in progress. The irinotecan/cisplatin combination has considerable activity in the second-line setting. Randomized trials comparing this combination to docetaxel are needed. Irinotecan is an active agent in the first- and second- line therapy of NSCLC.
Clin Lung Cancer 2002 Nov
PMID:The role of irinotecan combined with Cisplatin or Carboplatin in the treatment of advanced non-small-cell lung cancer. 1465 34


<< Previous 1 2 3 4 5 6 Next >>