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)

Mutations and reduced expression of DNA topoisomerase I (topo I) gene have been shown to be important in the acquisition of resistance to camptothecin and its analogues in vitro, but their significance has not been verified in vivo. We investigated possible topo I gene mutations and topo I mRNA expression levels in 127 samples obtained from 56 patients with lung tumors, including patients who had developed clinical resistance to topo I inhibitors. No mutations were detected in any of the samples examined and expression levels did not differ significantly between clinically resistant cases and others. However, the topo I mRNA expression level was significantly higher in small cell lung carcinomas than in non-small cell lung carcinomas (P < 0.05). These results suggest that topo I mRNA levels may affect CPT-11 sensitivity in human lung cancer. However, topo I gene mutations and reduced topo I mRNA expression may not be the main mechanism of clinically acquired resistance to camptothecin analogues in vivo.
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PMID:No alteration in DNA topoisomerase I gene related to CPT-11 resistance in human lung cancer. 904 64

To determine the optimal combination of commonly used anticancer agents with 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of 7-ethyl-10-[4(1-piperidino)-1-piperidino] carbonyloxy camptothecin (CPT-11), for chemotherapy of lung cancer, we studied the effects of SN-38 in combination with six representative anticancer agents on the human small cell lung cancer (SCLC) cell line, NCl N417, and the non-small cell lung cancer (NSCLC) cell line, PC-9. The anticancer activity was evaluated by MTT assay and the effects of drug combinations on ID50 were analyzed by an improved isobologram method. In the SCLC cell line, supra-additive effect was observed for SN-38 in combination with cisplatin, etoposide (VP-16) and paclitaxel (Taxol). An additive effect was observed for its combination with bleomycin. Sub-additive and protective effects were found in combination with adriamycin (ADR) and 5-fluorouracil (5-FU). In the NSCLC cell line, supra-additive and marginal supra-additive effects were found for SN-38 in combination with VP-16, ADR, 5-FU and bleomycin. The others showed additive effects with SN-38. No drug showed sub-additive and protective effects with SN-38. These results suggest that all the drugs we selected can be used with SN-38 simultaneously for NSCLC, while for SCLC, cisplatin, VP-16 and Taxol are the most suitable for combination with SN-38.
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PMID:Effect of CPT-11 in combination with other anticancer agents in lung cancer cells. 909 27

Oxaliplatin is a new platinum analog of the DACH family. Recent preclinical data have confirmed its non overlapping spectrum of activity with cisplatin, including acquired and intrinsic platinum resistant cell lines (as KB-CP, A 2780, HT29, CaCo2 colon cancer). When combined with other cytotoxic agents (5FU, SN38, CDDP, carboplatin), oxaliplatin has additive and/or synergistic antitumoral effects on various in vitro and in vivo models (colon, breast, ovarian and epidermoid tumors). Phase II trials have confirmed a sensorial peripherical neuropathy as its limiting toxicity while neither ototoxicity nor renal toxicities and only limited myelotoxicity were noted. Available phase II studies have established its antitumoral activity as single agent in 5FU refractory colon carcinoma while preliminary results suggest efficacy in cisplatin resistant ovarian cancer, in non small cell lung cancer, non Hodgkin lymphoma. Antitumoral activity has been observed during phases 1 in melanoma, glioma, breast and oesophageal cancers. A high response rate (28-65%) with the triple association (FU/folinic acid/oxaliplatin) has been reported in advanced colon cancer treated in first and second line settings. The results of two randomized phase III studies (FU/folinic acid +/- oxaliplatin) are expected. The oxaliplatin/cisplatin combination as salvage regimen had produced significant antitumoral activity (response rate: 45%) in resistant/refractory ovarian cancer. Finally, recent experimental and clinical data have outlined the potential interest in the development of this new original platinum compound. New single agent phases II are expected in other tumor types as well as new oxaliplatin combinations are ongoing (phase I trials of oxaliplatin/CPT-11 and of oxaliplatin/carboplatin, phase II study of oxaliplatin-vinorelbine in lung cancer.
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PMID:[Oxaliplatin: the first DACH platinum in clinical practice]. 929 71

Prevention of cigarette smoking and early lung cancer detection remain important in our approach to the control of non-small cell lung cancer (NSCLC). In recent years, chemotherapy has emerged as a viable option in the treatment of NSCLC. The most impressive and widely confirmed evidence for this is the fact that chemotherapy can eradicate NSCLC micrometastases. Indeed, in some studies employing neoadjuvant chemotherapy followed by local surgery, pathology-confirmed complete remission rates as high as 20% have been reported. New agents showing preliminary activity in NSCLC include paclitaxel, vinorelbine, gemcitabine, and irinotecan (CPT-11). Certainly, however, there remains a need for novel, effective single-agent and combination chemotherapies. The seed/soil tumor concept, in which the seed consists of the tumor cells per se and the soil is the stroma containing the seeds, has proven helpful in devising new treatment strategies. Such strategies may include the use of antisoil agents, including antiangiogenesis, anti-invasion, and antimetastasis agents, both separately and particularly in conjunction with established antitumor agents. New therapeutic targets and methods of antitumor agent development based on modern molecular biology and pharmacology will provide a greater opportunity to improve the treatment of NSCLC.
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PMID:Non-small cell lung cancer: novel treatment strategies. 933 1

Recently, a number of novel chemotherapeutic agents under development show consider able promise in the treatment of lung cancer. Optimally, these new agents should exhibit a unique mechanism of action, a favorable toxicity profile in comparison to standard cisplatin-based chemotherapy, significant single agent activity (> 20% response rate, or > 40% 1-year survival rate) and synergistic antitumor effects with cisplatin and/or radiation. This review will describe the current development status of these new agents, including paclitaxel, docetaxel, vinorelbine, CPT-11, topotecan and gemcitabine.
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PMID:[Lung cancer]. 935 Feb 36

The efficacy of systemic chemotherapy (CDDP + IFO + 5-FU or CDDP + IFO + CPT-11) was evaluated in 41 patients with malignant pleural effusion secondary to adenocarcinoma of the lung. The overall response rate for measurable disease was 56.1%. The response for pleural effusion was evaluated according to the criteria of the Japan Lung Cancer Society. The overall response for pleural effusion was 53.7% (34.1% CR and 19.5% PR). The median survival time was 361 days. These results suggested that systemic chemotherapy is an effective treatment for pleuritis carcinomatosa.
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PMID:[Efficacy of systemic chemotherapy in adenocarcinoma of the lung with pleuritis carcinomatosa]. 935 Feb 47

We conducted a phase I study of irinotecan (CPT-11) and etoposide (VP-16) given sequentially to untreated patients with metastatic non-small-cell lung cancer. Arm A: CPT-11 was given over 90 min on days 1-3 and VP-16 was given over 60 min on days 4-6. Arm B: VP-16 was given on days 1-3 and CPT-11 on days 4-6. G-CSF was given to all patients daily on days 7-17. Twenty-seven patients were entered randomly at the two arms. The major dose-limiting toxicities in arms A and B were granulocytopenia and diarrhoea. Transient elevations of transaminases and bilirubin were observed in both arms. The degree of the toxicities did not differ between the two arms. The maximum tolerated doses (MTDs) were 60 mg m-2 CPT-11 and 60 mg m-2 VP-16 in both arms. Of the 13 patients who received more than two cycles, two out of five achieved partial response (PR) at the first level of arm A and one out of four achieved PR at the second level of arm B. We conclude that these schedules of sequential CPT-11 and VP-16 administration were inappropriate because of severe toxicities.
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PMID:Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung cancer. 940 Sep 32

Although glucuronidation catalyzed by uridine 5'-diphosphoglucuronosyltransferase (UGT) is a major pathway of drug inactivation in humans, glucuronidation in malignant cells has received little attention as a cause of anti-cancer drug resistance. In this study, we tried to elucidate the role of SN-38 glucuronidation in the CPT-11-resistant human lung cancer cell line PC-7/CPT. PC-7/CPT cells possessed an increased activity to glucuronidate SN-38 compared to the parent cells, PC-7. Furthermore, sensitivity of PC-7/CPT cells to SN-38 was improved by inhibiting UGT activity. Western and northern blot analyses demonstrated that this increased activity was due to increased levels of UGT protein and mRNA. These results not only imply that upregulation of UGT activity in PC-7/CPT cells may contribute in part to SN-38 resistance, but also illustrate the important of drug metabolism within malignant cells themselves, as a cause of drug resistance.
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PMID:The role of glucuronidation in 7-ethyl-10-hydroxycamptothecin resistance in vitro. 947 40

We evaluated the mobilization of peripheral blood stem cells (PBSCs) after the administration of chemotherapy including irinotecan (CPT-11) in individuals with advanced thoracic malignancies including lung cancer and mesothelioma. All patients were previously untreated. The numbers of CD34+ cells, CD34+ 38- cells, and colony-forming units granulocyte-macrophage (CFU-GM) in peripheral blood were determined to monitor PBSCs at least twice a week. Granulocyte colony-stimulating factor (G-CSF) (75 micrograms/body per day) was administered at the onset of neutropenia [absolute neutrophil count (ANC) of < 1000/microliter] until the ANC exceeded 5000/microliter. In patients who received G-CSF, sufficient counts of the PBSCs for PBSC transplantation were mobilized at the time when the white blood cell count was > 5000/microliter. CPT-11 with G-CSF is thus a promising induction regimen for PBSC transplantation. Patients who did not develop neutropenia after chemotherapy showed a significantly (p = 0.005) higher number of CD34+ cells in the peripheral blood at steady state (median, 1818; range, 1534 to 4433; n = 8) than those who developed neutropenia (median, 666; range, 608 to 1553; n = 5). This parameter may thus prove a useful marker for predicting neutropenia after the administration of CPT-11.
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PMID:Mobilization of peripheral blood stem cells in patients with advanced thoracic malignancies after irinotecan (CPT-11) administration. 956 66

Irinotecan (CPT-11) is a semisynthetic camptothecin derivative with a broad spectrum of anti-tumour activity. Carboxylesterase (CE) catalyses the conversion of CPT-11 to SN-38 (7-ethyl-10-hydroxycamptothecin), the active form of CPT-11. The antiproliferative effects of CPT-11 and SN-38, CE-activity and topoisomerase I protein expression were investigated in five human small-cell lung cancer (SCLC) cell lines and four human non-small-cell lung cancer (NSCLC) cell lines. Antiproliferative activity, expressed as IC50 values, was determined using the MTT assay. CPT-11 was significantly more active in SCLC than in NSCLC cell lines (P = 0.0036), whereas no significant difference between histological types was observed with SN-38. A significant correlation (r2 = 0.52, P = 0.028) was observed between CE activity and chemosensitivity to CPT-11 but not to SN-38, and significantly higher CE activity was observed in SCLC compared with NSCLC cell lines (P = 0.025). Western blotting experiments showed topoisomerase I protein expressions within a factor of 2, and a granular nuclear staining was detectable in all cell lines by immunocytochemistry of cytospins. No correlation was observed between protein expression and sensitivity to CPT-11 or SN-38. Cellular and medium concentrations of CPT-11 and SN-38 were measured by high-performance liquid chromatography (HPLC) in one SCLC cell line with high CE activity and high sensitivity to CPT-11, and one NSCLC cell line with low sensitivity to CPT-11 and CE activity. Intracellular concentrations of CPT-11 and SN-38 were higher in the SCLC cell line, and this was associated with an increase in cellular uptake of CPT-11 compared with the medium, and an increased intracellular formation of SN-38. In conclusion, CE activity appears to be associated with higher sensitivity to CPT-11 in human lung cancer cell lines and may partly explain the difference in the in vitro sensitivity to CPT-11 between SCLC and NSCLC cells. The assessment of CE activity in clinical material of lung cancer patients undergoing treatment with CPT-11 may be warranted. However, other mechanisms may influence sensitivity to CPT-11, possibly including drug transport.
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PMID:Determinants of CPT-11 and SN-38 activities in human lung cancer cells. 964 29


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