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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence indicates that individuals with a p53 germ-line mutation (Li-Fraumeni syndrome) have a 50% risk of developing lung cancer by age 60. In this study, p53 heterozygous knockout mice and p53 transgenic mice carrying a dominant negative mutant were crossed with the A/J mouse, which is highly susceptible to lung tumor induction, to investigate whether a p53 germ-line mutation is a predisposing gene for carcinogen-induced pulmonary adenomas in mice. The number of lung tumors was not significantly increased in (TSG-p53 x A/J)F1 p53 heterozygous knockout mice as compared with that in (TSG-p53 x A/J)F1 wt mice 16 weeks after exposure to N-nitrosomethylurea (MNU). In contrast, an average of 22 lung tumors were observed in (UL53-3 x A/J)F1 mice carrying a mutant p53 transgene (135Valp53) compared with an average of 7 lung tumors seen in (UL53-3 x A/J)F1 wt mice after treatment with N-nitrosomethylurea. Similar enhancement of lung tumor multiplicity (approximately 3-fold) was seen when mutant versus wt mice were treated with the tobacco-related carcinogens benzo[a]pyrene or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest that the mutant p53 transgene may have a dominant negative effect on the wt p53. The potential usefulness of this new mouse model in lung cancer chemoprevention and chemotherapy was examined. The chemopreventive efficacy of the green tea or a combination of dietary dexamethasone and myoinositol and the chemotherapeutic efficacy of Taxol or Adriamycin was examined in wt mice or mice with a mutation in the p53 gene. Mice treated with dexamethasone/myo-inositol and green tea displayed an average of 70 and 50% inhibition of lung tumors, respectively, regardless of p53 status. Similarly, when mice bearing established lung adenomas were treated with Taxol or Adriamycin, a decrease in tumor volume of approximately 70% was observed independent of p53 mutation status. Thus, the (UL53-3 x A/J)F1 p53 transgenic mouse seems to be an excellent model for human carriers of p53 germ-line mutations (Li-Fraumeni syndrome). Furthermore, the lung adenomas generated in this model possess mutations in both the K-ras proto-oncogene and the p53 tumor suppressor gene. This model should prove directly useful for chemoprevention and chemotherapy studies.
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PMID:A germ-line p53 mutation accelerates pulmonary tumorigenesis: p53-independent efficacy of chemopreventive agents green tea or dexamethasone/myo-inositol and chemotherapeutic agents taxol or adriamycin. 1070 3

Irinotecan(CPT-11), Taxol, Taxotere, vinorelbine and gemcitabine have shown a significant activity in previously untreated non-small cell lung cancer (NSCLC). Cisplatin(CDDP) combined with vinorelbine, gemcitabine or tirapazamine was significantly superior in survival to CDDP alone in the treatment of advanced NSCLC. Patients with NSCLC treated with combination of CDDP and Taxol or vinorelbine lived longer than those treated with conventional CDDP-based chemotherapy. CPT-11, topotecan, taxol and amrubicin have demonstrated to be active against small cell lung cancer(SCLC). Combination of CPT-11 and CDDP have had a higher response rate, and better median survival(13 months) in patients with extensive disease SCLC. Clinical trials of target-based drugs including matrix metalloprotenase inhibitors, anti-angiogenesis, tyrosine kinase inhibitors, farnesyl transferase inhibitors and monoclonal antibodies have been initiated in solid tumors including lung cancer. Development of new anti-cancer agents is essential to improve outcomes of patients with lung cancer.
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PMID:[Current perspectives of new agents in lung cancer]. 1082 57

The purpose of this study was to evaluate the combination of gemcitabine (Gemzar), paclitaxel (Taxol), and carboplatin (Paraplatin) in patients with advanced non-small-cell lung cancer (NSCLC). Previously untreated patients with stage IIIB or IV NSCLC were included in this trial. A total of 69 patients from the phase II portion and 8 patients from the phase I portion were treated with gemcitabine 1,000 mg/m2 intravenously (i.v.) on days 1 and 8; paclitaxel 200 mg/m2 as a 1-hour infusion on day 1; and carboplatin at an area under the curve (AUC) dose of 5.0 i.v. on day 1. Treatment courses were repeated every 21 days. The phase II component of the study was completed at 13 community-based practices within the Minnie Pearl Cancer Research Network. Of the 71 fully evaluable patients, 34 had an objective response, for an overall response rate of 48%; 2 patients showed complete responses and 32 patients had partial responses. A total of 25 (35%) patients were stable and 12 (17%) patients progressed. The median response duration was 6 months (range 3 to 14 months), and the median survival was 9.9 months, with a 1-year survival of 47% and a 2-year survival of 21%. These results show that the combination of gemcitabine, paclitaxel, and carboplatin is safe and effective; however, randomized phase III studies are needed to prove this regimen is superior to other regimens.
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PMID:Gemcitabine, paclitaxel, and carboplatin for advanced non-small-cell lung cancer. 1096 Sep 43

In our previous phase I/II studies, both the cisplatin (Platinol), gemcitabine (Gemzar), and vinorelbine (Navelbine) (PGV), and cisplatin, gemcitabine, and paclitaxel (Taxol) (PGT) regimens produced a median survival of approximately 1 year in patients with advanced non-small-cell lung cancer (NSCLC). The present phase III study compared the median survival of patients treated with these triple-drug regimens to that of patients receiving cisplatin plus vinorelbine (PV) or cisplatin plus gemcitabine (PG). Accrual for the trial began in 1997 and by December 1998, a total of 240 patients (stage IIIB, 98; stage IV, 142) had been enrolled. An interim survival analysis was performed in April 1999. Overall, 151 patients had died. The median survival rates of patients in the PGV, PG, and PV arms were 51, 42, and 35 weeks, respectively. At the time of this analysis, the median survival of patients in the PGT arm could not be assessed; however, the 1-year projected survival rate was 58%. At multivariate Cox analysis, the estimated risk of death for patients receiving PGV compared with those receiving PV was 0.35 (95% CI, 0.16-0.77, P = .0058). Overall response rates were 47% in the PGV arm, 30% in the PG arm, 25% in the PV arm, and 58% in the PGT arm. Severe neutropenia and vomiting were significantly more frequent in patients who received PV than in those who received PGV. The PV regimen produced a significantly shorter survival compared with the PGV combination. Since this difference in survival complied with one of the early stopping rules, accrual in the PV arm was discontinued. Enrollment in the PGV, PG, and PGT arms is ongoing.
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PMID:Interim analysis of a phase III trial. Triple- vs double-agent chemotherapy for advanced non-small-cell lung cancer. Southern Italy Cooperative Oncology Group. 1096 Sep 44

The Hellenic Cooperative Oncology Group conducted a randomized phase III trial to compare paclitaxel (Taxol) 200 mg/m2 i.v. 3-hour infusion on day 1 plus carboplatin (Paraplatin) at an area under the curve (AUC) of 6 (group A) with paclitaxel at the same dose plus gemcitabine (Gemzar) 1,000 mg/m2 on days 1 and 8 (group B) every 3 weeks for a maximum of six cycles in patients with advanced non-small-cell lung cancer. To date, 127 eligible patients have been randomized, 63 to group A and 64 to group B, and median follow-up is 4.6 months. Preliminary results suggest that both combinations are well tolerated and can be administered at full doses. Grade 3-4 neutropenia was generally mild but more prominent in group A (10%) and thrombocytopenia was insignificant in both groups. Severe neurotoxicity, hepatotoxicity, or cardiac toxicity have not been recorded in the majority of patients in either group. There was a trend toward higher response rates in favor of group B (group B vs group A, 37.5% vs 21.8%, respectively), although time-to-disease progression did not differ significantly (group B vs group A, 7.25 vs 7.1 months, respectively). Further maturation of the study is needed before definitive conclusions can be drawn.
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PMID:Interim results of a phase III trial. Paclitaxel/carboplatin vs paclitaxel/gemcitabine in advanced non-small-cell lung cancer. 1096 Sep 45

Over the last decade, a group of new agents with differing mechanisms of action have shown great promise in early clinical studies in non-small-cell lung cancer (NSCLC). These include the taxanes docetaxel (Taxotere) and paclitaxel (Taxol); the nucleoside analog gemcitabine (Gemzar); the vinca alkaloid vinorelbine (Navelbine); the topoisomerase-I inhibitor irinotecan (Camptosar, CPT-11); and the bioreductive agent tirapazamine. Cisplatin (Platinol), which has been the "backbone" of combination chemotherapy in patients with NSCLC because of its proven single-agent activity, has been examined in combination with these agents as well as radiation and surgery in numerous trials. This article summarizes trials of these combination therapies in the treatment of NSCLC.
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PMID:Chemotherapy in metastatic non-small-cell lung cancer. 1098 Dec 87

This multicenter study enrolled 73 patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). The study design was based on the hypothesis that the non-overlapping toxicities of a 3-drug combination of irinotecan (Camptosar, CPT-11), carboplatin (Paraplatin), and paclitaxel (Taxol) would allow them to be dosed at recommended or standard doses, respectively. Of the 32 patients in phase I portion of the trial, six received irinotecan 40 mg/m2 plus carboplatin at an area-under-curve (AUC) of 6 and paclitaxel 225 mg/m2 on an every-3-week schedule (regimen A). Due to the unexpectedly severe toxicity associated with this regimen, the carboplatin and paclitaxel doses were reduced, while the irinotecan doses were escalated from 40 to 80 to 125 mg and reduced to 100 mg/m2 (regimen B). In the phase II portion of the trial, irinotecan was dosed at 100 mg/m2 because 3 of 8 patients who received the 125 mg/m2 dose in phase I experienced first-course grade 3/4 toxicities. However, the toxicity of regimen B proved unacceptably severe in phase II; 13 of the 40 patients (35%) experienced grade 3/4 neutropenia and 30% suffered febrile or septic neutropenia. The unconfirmed objective response rate in phase I was 64.5%; median time to progression and median survival were 7.1 months and 11.6 months, respectively, and 1-year survival was 46.9%. The unconfirmed objective response rate in phase II was 60.6%, including one complete response (CR) and 19 partial responses (PRs); one CR and 16 PRs were subsequently confirmed. The efficacy and toxicity of this triple combination strongly suggest significant pharmacokinetic and/or pharmacodynamic interactions, warranting continued clinical investigation.
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PMID:Phase I/II trial of irinotecan, carboplatin, and paclitaxel in advanced or metastatic NSCLC. 1098 Dec 88

This phase I/II nonrandomized, open-label study was designed to assess the safety and benefit of sequencing irinotecan (Camptosar, CPT-11) plus paclitaxel (Taxol) immediately after cisplatin (Platinol)/etoposide (VePesid, VP-16) or carboplatin (Paraplatin)/etoposide in patients with extensive small-cell lung cancer (SCLC). Ten patients were evaluable in phase I; all had previously been treated with cisplatin and etoposide, and five of the 10 had also previously received carboplatin and paclitaxel. All 10 patients were given a fixed dose of irinotecan (60 mg/m2) and escalating doses of paclitaxel weekly for 3 weeks. Three patients had grade 4 toxicities, one at the lowest dose level of paclitaxel (15 mg/m2). Two patients had grade 3 toxicities. The dose-limiting toxicity occurred at the 60 mg/m2 paclitaxel dose level, when the performance status of both patients in that group decreased to 60 (Karnofsky scale). Two patients had progressive disease after 1 month of treatment and did not receive cycle 2. Three of seven patients evaluable for response had complete remissions. A fourth patient had resolution of lymphangitic metastases and resolution of a partial small bowel obstruction but did not have measurable disease. The fifth patient had a partial remission. The ongoing phase II portion of the study is restricted to previously untreated patients who will receive at least one cycle of either cisplatin or carboplatin in combination with etoposide followed by irinotecan at 60 mg/m2 and paclitaxel at 50 mg/m2 dosed once weekly for 3 weeks.
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PMID:Phase I/II study of weekly irinotecan and paclitaxel in patients with SCLC. 1098 Dec 93

The tumor suppressor gene p53 is perhaps the most commonly mutated gene in human cancer, being mutated in a high percentage of colon, breast, skin, bladder, and many cancers of the aerodigestive tract. Individuals with Li-Fraumeni syndrome, who routinely have a germline mutation in the p53 tumor suppressor gene, are at high risk for lung cancer, confirming its intimate role in lung tumorigenesis in humans. In contrast, the majority of chemically induced or spontaneous cancers in rodents do not contain mutations in p53. Therefore, we examined a transgenic mouse that contains a dominant negative mutation (Arg135Val) in the p53 gene placed under the control of its own endogenous promoter. The resulting mice have 3 copies of the mutated transgene as well as 2 normal p53 alleles. In the chemical carcinogenesis studies, we employed mice containing the mutated p53 gene to examine for carcinogen susceptibility. We found that mice with the p53 mutation, on an A/J F1 background, were more susceptible to a number of potential lung carcinogens, including N-methyl-N-nitrosourea (MNU) and the known tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BP). Mice with a mutant p53 developed larger tumors and roughly 3 times as many tumors, emphasizing the potential effects of a p53 mutation both on tumor initiation and progression. In addition, we examined 2 nonlung carcinogens, 1,2-dimethylhydrazine (DMH), a colon carcinogen, and N-butyl-N-(4-hydroxybutyl)-nitrosamine (OHBBN), a bladder carcinogen. Interestingly a germline p53 mutation increased the incidence of DMH-induced colon, lung, hepatic, and uterine tumors, while having limited effects on OHBBN-induced bladder tumors. Because of its heightened susceptibility we are examining the use of this model in smoke-induced tumorigenesis in A/J mice as well. Employing the lung adenomas induced by NNK, we found that mice with or without a p53 mutation were equally susceptible to the chemopreventive effects of dexamethasone plus myo-inisitol and green tea. These tumors, which arise in a highly reproducible manner in p53 transgenic mice following carcinogen treatment, have mutations in both p53 and the K-ras oncogene. Thus, this model appears useful for examining for potential chemotherapeutic agents. p53-mutated or wild-type mice were equally susceptible to the therapeutic effects of Taxol or Adriamycin. Interestingly, piroxicam was similarly effective in inhibiting colon tumor formation by DMH in mice with or without a mutation in the p53 tumor suppressor gene. In contrast, lung and uterine tumors developing in these mice were not susceptible to the chemopreventive effects of piroxicam. In summary, mice with mutations in the p53 tumor suppressor gene appear to be particularly applicable for basic mechanistic studies, for screening for potential carcinogens, and for screening for chemopreventive or chemotherapeutic agents.
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PMID:Use of p53 transgenic mice in the development of cancer models for multiple purposes. 1119 57

There will be approximately 40,000 new cases of small-cell lung cancer this year. Prior to 1990, there were several agents with single-agent response rates of 30% to nearly 90% in the untreated small-cell lung cancer population and approximately 10% to 20% in relapsed patients. During the 1990s, several new chemotherapy agents have displayed activity in small-cell lung cancer (paclitaxel [Taxol], gemcitabine [Gemzar], vinorelbine [Navelbine], topotecan [Hycamtin], and irinotecan [Camptosar, CPT-11]). The majority of studies with irinotecan have been conducted in Japan. The US experience is limited to a single multi-institution trial that was conducted in patients with previously treated small-cell lung cancer. A total of 44 patients were entered in the study. Patients were stratified by response to prior therapy. Responses occurred in 7 of 44 patients for an overall response rate of 14%. The overall median survival was 4.8 months.
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PMID:Irinotecan in small-cell lung cancer: the US experience. 1122 Oct 15


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