Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The responses of 14 lines of human lung cancer xenografts in BALB/c-nu/nu mice to eight known antitumor agents were investigated. These xenografts consisted of four small-cell carcinomas (SCLC) and ten non-small-cell carcinomas (four large cell, three squamous cell, and three adenocarcinomas; NSCLC). The doses used in the experiments were the maximum tolerated dose (MTD) in nude mice and the "rational dose" (RD), the latter considered to be pharmacokinetically equivalent to the clinical dose. When given at MTDs, all drugs except 5-fluorouracil (5-FU) and methotrexate (MTX) were extremely effective against NSCLC as well as SCLC. The response rates of drug-sensitive SCLC to mitomycin C (MMC), ACNU, and vinblastine (VLB) were 100%, and those to Adriamycin (ADR) and vincristine (VCR) were 75%. In addition, the response rates of even drug-resistant NSCLC to MMC and VLB were 70% and 90%, respectively. In contrast, the response rates of NSCLC to RDs of the drugs were reduced to less than 40% and corresponded well to the respective clinical rates. In SCLC, a good correlation of experimental and clinical response rates was observed with four drugs [cyclophosphamide (CPM), ACNU, VLB, and 5-FU]. As a result, we emphasize that a more reasonable prediction of the clinical effectiveness of antitumor agents can be made by a protocol using clinically equivalent doses.
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PMID:Responsiveness of human lung cancer/nude mouse to antitumor agents in a model using clinically equivalent doses. 254 8

The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and overall survival (P = .098 Wilcoxon test) were higher on MACC + W (median, 6.6 months and 9.3 months, respectively), as compared with MACC (5.0 months and 7.9 months) and MEPH/MACC (5.0 months and 7.9 months). Toxicity was comparable among the three arms, except for increased hemorrhagic events on MACC + W, which were life-threatening in four patients (4%), and lethal in two others (2%). These data support the role of warfarin in the treatment of SCCL, but do not establish its mechanism of action. Warfarin deserves further studies in SCCL, particularly in patients with limited disease.
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PMID:A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. 215 91

A range of anthracyclines and related compounds were evaluated for activity against murine and human cell lines exhibiting multidrug resistance (MDR). Cell lines used were the NCI-H69 human small-cell lung cancer line and the EMT6 murine mammary tumour line, together with their multidrug-resistant counterparts produced by in vitro exposure to Adriamycin (ADM). Chemosensitivity testing was carried out using the tetrazolium (MTT) dye assay. Results were expressed as the ratio of the ID50 for the resistant line to that obtained in the parent, i.e. the resistance factor (RF). Compounds exhibiting much lower RF values than ADM in both resistant cell lines were identified as those anthracyclines with 9-alkyl substituents and those with certain changes to the amino sugar residue at position 3' and 4', together with the anthracenedione mitoxantrone (MIT). In a further attempt to overcome resistance, we used four of these compounds, Ro 31-1215, 4'-deoxy-4'-iodo-ADM (iodo-ADM), aclacinomycin A (ACL) and MIT (all yielding low RF values), in combination with the resistance modifiers verapamil (VRP) and cyclosporin A (CYA). Additional enhancement of chemosensitivity was achieved in the ADM-resistant sublines, as shown by the further decrease in RF values. At the concentrations used, the largest effects were generally seen with CYA, and the combination of this modifier with ACL and MIT was particularly effective. For the H69/LX4 resistant line, the latter combinations gave RF values approaching unity. These findings point to the use of analogues with the 9-alkyl substituent and/or specific changes to the sugar residue in combination with resistance modifiers as a therapeutic strategy for circumvention of the MDR phenotype.
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PMID:Identification of anthracyclines and related agents that retain preferential activity over adriamycin in multidrug-resistant cell lines, and further resistance modification by verapamil and cyclosporin A. 254 27

Fourteen patients with extensive-disease non-small-cell lung cancer (E-NSCLC) were treated with oral 4-demethoxydaunorubicin (idarubicin, 4DMDR) at a dosage of 10 mg/m2/day x 5 days every 3 weeks. The median cumulative dose was 110 mg/m2 (range: 50-1,100). Two patients had stable disease for 12 and 56 weeks, respectively, one patient had failed to respond to a doxorubicin hydrochloride (Adriamycin)-containing regimen, and one had had no prior therapy. Twelve of the 14 patients had prior radiotherapy, chemotherapy, or both. Median survival for this heavily treated group was 16 weeks. Myelosuppression was minimal. Nausea and vomiting occurred in 44% of all courses. No cardiac toxicity and no decrease in cardiac ejection fraction was observed. We conclude that 4DMDR is ineffective in heavily treated E-NSCLC patients. However, the drug's activity in untreated patients is unknown. Further study of 4DMDR is indicated in patients who have had no prior chemotherapy or radiotherapy, with routine administration of antiemetic drugs along with pharmacokinetic studies.
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PMID:Phase II study of idarubicin in extensive-disease non-small-cell lung cancer. 255 12

A total of 144 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin/etoposide (PE) or ifosfamide/etoposide (IE) combination chemotherapy. PE consisted of cisplatin, 80 mg/m2, intravenously (IV) on day 1, and etoposide, 150 mg/m2, IV on days 3 through 5. IE consisted of ifosfamide, 1,500 mg/m2, IV on days 1 through 5, and etoposide, 120 mg/m2, IV on days 3 through 5. Six cycles were administered in 3-week intervals. Nonresponders were switched immediately to CAV, consisting of cyclophosphamide, 600 mg/m2, IV on days 1 and 2, Adriamycin (Adria Laboratories, Columbus, OH), 50 mg/m2, IV on day 1, and vincristine, 2 mg, IV on day 1. Patients obtaining complete remission (CR) received prophylactic cranial irradiation with 30 Gy. After completion of chemotherapy, patients with limited disease received chest irradiation with 45 Gy. No maintenance therapy was given to patients in CR. Minimum follow-up was 2 years. Of the 141 patients evaluable, the overall response rate was 65% in PE therapy and 68% in IE therapy. The CR rate was 32% v 20% for all patients, 50% v 24% for limited disease, and 22% v 18% for extensive disease, all in favor of PE therapy. Median survival for all patients was 11.6 months v 9.4 months, for limited disease 14.8 months v 11.0 months, and for extensive disease 8.9 months v 7.5 months, all preferring PE therapy. The 2-year survival rate was higher in PE therapy than in IE therapy for all patients (12% v 9%) and for limited disease (23% v 10%), but not for extensive disease (5% v 9%). Median progression-free survival was 7.5 months v 6.0 months for all patients, 12.2 months v 8.8 months for limited disease, and 5.9 months v 4.4 months for extensive disease, all in favor of PE. Relapse in the area of the primary tumor was found less often after PE than after IE therapy (25% v 38%). Response to second-line CAV was seen in 30% of patients with prior PE and 43% with prior IE therapy, but was usually short lasting, and only one patient achieved CR. Toxicity included three lethal complications. Nausea, vomiting, diarrhea, and skin lesions occurred more often after PE than after IE therapy. These results suggest that PE is superior to IE chemotherapy in limited-stage, but not in extensive-stage SCLC, and that CAV is cross-resistant to PE, as well as to IE in the majority of patients.
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PMID:Cisplatin/etoposide versus ifosfamide/etoposide combination chemotherapy in small-cell lung cancer: a multicenter German randomized trial. 282 10

From June 1982 through October 1985, the Southeastern Cancer Study Group randomized patients with limited small-cell lung cancer (SCLC) to cyclophosphamide plus doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) plus vincristine (CAV) for six cycles v CAV plus concomitant thoracic irradiation as induction therapy. Patients achieving either a complete or partial response and remaining in remission after completion of induction therapy were subsequently randomized to consolidation chemotherapy consisting of cisplatin 20 mg/m2 X 4 plus etoposide (VP-16) 100 mg/m2 X 4 every 4 weeks for two courses v no further therapy. There were 160 patients entered on the consolidation phase and 148 were fully evaluable. The median survival for patients randomized to cisplatin plus VP-16 (PVP16) from start of CAV chemotherapy was 97.7 weeks, compared with 68 weeks for the no-consolidation arm (P = .0094). PVP16 consolidation also significantly increased the duration of remission, with median durations of 49 weeks v 28 weeks (P = .0008). The median durations for partial remission were 41 weeks v 23 weeks (P = .013), and for complete remission, 52 weeks v 30.5 weeks (P = .0091). Furthermore, 18 patients on PVP16 consolidation remain in a continuous complete remission for 12+ months and 13 of these are continuously disease free 2+ years. Eight patients randomized to no consolidation remain in a continuous complete remission, with only four patients disease free 2+ years. PVP16 consolidation has significantly improved the duration of remission and overall survival and appears capable of improving the cure rate in limited SCLC.
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PMID:Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin, and vincristine in limited small-cell lung cancer. 283 49

Surgery alone is inadequate therapy for limited small-cell lung cancer (SCLC), resulting in less than 5% long-term survival. Since 1976, we treated patients undergoing surgery for SCLC with adjuvant chemotherapy in an attempt to prolong survival and increase cure. Seventy-seven patients who underwent surgery as their primary treatment were identified, and of these 63 (46 male and 17 female) received chemotherapy. Fifteen patients had a pneumonectomy, 46 a lobectomy, and two had wedge resections. Six patients had positive microscopic resection margins. Pathologic staging showed tumor, node, metastasis (TNM) involvement as follows: T1N0, eight; T2N0, ten; T1N1, six; T2N1, 18; T1N2, five; T2N2, nine; T3N0, three; T3N1, one; and T3N2, three. All patients received cyclophosphamide, Adriamycin (doxorubicion; Adria Laboratories, Mississauga, Ontario), and vincristine; four also received etoposide (VP-16) and cisplatin, one VP-16, and four methotrexate, procarbazine, and lomustine (CCNU). Forty-nine patients received prophylactic cranial irradiation, and 35 received radiotherapy to the mediastinum and primary site. The overall median survival of the 63 patients is 83 weeks, and the projected 5-year survival is 31%. Patients with T1 or T2 tumors without nodal involvement had a median survival of 191 weeks, and projected 5-year survival of 48%. Stage II (T1N1, T2N1) and stage III (any T3 or T1-2N2) patients had median survivals of 72 weeks and 65 weeks, and projected 5-year survivals of 24.5% and 24%, respectively. Thirty-three patients have relapsed and died of disease. Only two patients had an isolated relapse at the primary site. Seven other patients have died without recurrent disease. Adjuvant chemotherapy after surgery results in prolonged survival and cure for a significant number of patients with stage I SCLC, although nodal involvement at any level is associated with shorter survival.
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PMID:Adjuvant chemotherapy following surgical resection for small-cell carcinoma of the lung. 283 43

An economic evaluation of a randomized trial of cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and vincristine alone or alternating with etoposide (VP-16) and cisplatin in extensive small-cell lung cancer (SCLC) was undertaken. A survival benefit of 1.6 months in favor of alternating chemotherapy was associated with an additional cost of $450 (1984 Canadian dollars) per patient. This translated to a cost of $3,370 per year of life gained. Sensitivity analyses demonstrated that the cost-effectiveness (CEA) of alternating chemotherapy was greatest when treatment was given on an outpatient basis. The results of the evaluation were sensitive to hospitalization rates, but even the most unfavorable analyses revealed the CEA of alternating chemotherapy to be comparable to that of treatments of common nonmalignant diseases. It is concluded that the CEA of alternating chemotherapy for SCLC was favorable when compared with accepted treatments for nonmalignant diseases. The survival benefit seen with alternating chemotherapy was felt to be clinically significant and alternating chemotherapy is recommended as routine therapy for extensive SCLC.
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PMID:Cost-effectiveness of cancer chemotherapy: an economic evaluation of a randomized trial in small-cell lung cancer. 284 11

The purpose of this trial was to investigate the impact of systemic combination chemotherapy on survival and recurrence patterns in incompletely resected non-small-cell lung cancer. Incomplete resection was defined as presence of residual tumor in the resection margin or by presence of metastasis in the highest paratracheal lymph node sampled during protocol-directed surgical staging of the mediastinum. One hundred seventy-two patients were randomized to receive either postoperative radiotherapy (RT) alone or postoperative RT plus chemotherapy with CAP (Cytoxan [cyclophosphamide; Bristol Myers, Evansville, IN], Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and Platinol [cisplatin; Bristol Myers]) for 6 months. One hundred sixty-four patients were eligible for analysis at a mean time since randomization of 3.7 years. The chemotherapy arm showed significantly longer recurrence-free survival (two-sided Mantel-Haenszel log rank test, P = .004). This difference holds true for nonsquamous patients (P = .01), and approaches significance for squamous patients as well (P = .08). There was a 14% difference in survival rate favoring the chemotherapy arm 1 year after randomization. Analysis of sites of recurrence showed a significant decrease in distant metastases in the chemotherapy arm. Median survival for the entire group was approximately 17 months, and 35% are alive 2 years after resection. Toxicity of treatment consisted of esophagitis (mild-moderate by Eastern Cooperative Oncology Group [ECOG] criteria) and predictable hematologic, gastrointestinal (GI), and skin toxicity expected from CAP.
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PMID:The benefit of adjuvant treatment for resected locally advanced non-small-cell lung cancer. The Lung Cancer Study Group. 289 98

A monoclonal antibody, MRK 16, specific to a human myelogenous leukemia cell line, K-562, and resistant to Adriamycin, was used to determine the localization of the antigen molecules (P-glycoprotein) recognized by the monoclonal antibody. P-glycoprotein was found to be expressed very strongly in the adrenal cortex and medulla of adults and strongly in the renal tubules of the kidney and the placenta. Interestingly, P-glycoprotein was not distributed in fetal and neonatal adrenals, and thus may be closely related to adrenal maturation. A high level of P-glycoprotein expression was also seen in one case each of untreated lung cancer (one of ten) and breast cancer (one of nine). Immunoelectron microscopically, the P-glycoprotein was distributed evenly on the membranes of K-562/ADM and 2780 cells. These results imply that the presence of the glycoprotein may be useful as a marker for in vitro studies of multidrug resistance in various malignancies and as an indicator of therapeutic efficacy of ex vivo eradication of multidrug-resistant cancer cells, although other mechanisms of drug resistance may exist, and there is a possibility that this MRK 16 monoclonal antibody may not recognize all P-glycoprotein.
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PMID:Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. 289 94


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