Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters.

Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model.

Association of ABCB1 polymorphisms with erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer.

Aims: We analyzed the association of ABCB1 polymorphisms with erlotinib-induced toxicity and the pharmacokinetics in patients with non-small-cell lung cancer.

Materials & Methods: After erlotinib 150 mg was administered to 50 patients, ABCB1 polymorphisms were analyzed via either TaqMan(®) assays or direct nucleotide sequencing. Plasma concentrations were measured by HPLC.

Relationship between functional preservation after segmentectomy and volume-reduction effects after lobectomy in stage I non-small cell lung cancer patients with emphysema.

Objectives: To evaluate whether functional preservation after segmentectomy has a greater advantage of pulmonary functions than volume-reduction effects after lobectomy in patients with emphysema with clinical T1N0 non-small cell lung cancer (NSCLC).

Patients And Methods: Between January 2000 and December 2006, 47 cases of lobectomy and 71 cases of segmentectomy were performed in patients with stage I NSCLC using intraoperative sentinel node identification. The postoperative change of the forced expiratory volume in 1 second (deltaFEV(1)) 6 months after segmentectomy was compared with that of 6 months after lobectomy.

Combined evaluation of postoperative serum levels of carcinoembryonic antigen less than or equal to 2.5 ng/ml and absence of vascular invasion may predict no recurrence of stage I adenocarcinoma lung cancer.

Study Objectives: It has been reported that high levels of serum carcinoembryonic antigen (CEA) after surgery, or the presence of vascular invasion or both, are strong indicators of postoperative recurrence in patients with non-small cell lung cancer. The purpose of this study is to evaluate which kind of patients with p-stage I adenocarcinoma need adjuvant chemotherapy, using those predictors.

Patients And Methods: We studied 136 patients with curatively resected p-stage I adenocarcinoma during the 7-year period of January 1, 2000 to December 31, 2006.

Role of P-glycoprotein in accumulation and cytotoxicity of amrubicin and amrubicinol in MDR1 gene-transfected LLC-PK1 cells and human A549 lung adenocarcinoma cells.

Amrubicin is a completely synthetic 9-aminoanthracycline agent for the treatment of lung cancer in Japan. The cytotoxicity of C-13 hydroxy metabolite, amrubicinol, is 10 to 100 times greater than that of amrubicin. The transporters responsible for the intracellular pharmacokinetics of amrubicin and amrubicinol remains unclear.

Pharmacokinetics of amrubicin and its active metabolite amrubicinol in lung cancer patients.

Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to characterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol.

Phase I and pharmacokinetic study of amrubicin, a synthetic 9-aminoanthracycline, in patients with refractory or relapsed lung cancer.

Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses.

Efficacy of the tyrosine kinase inhibitor gefitinib in a patient with metastatic small cell lung cancer.

Gefitinib (Iressa, ZD1839) is an orally active inhibitor selective for the epidermal growth factor receptor tyrosine kinase and has shown promise in the treatment of non-small cell lung cancer (NSCLC). There has been no report to date of the effect of gefitinib treatment in patients with small-cell lung cancer (SCLC). Here we report a case of metastatic SCLC that was successfully treated with gefitinib.

Synergistic tumor suppression by coexpression of FHIT and p53 coincides with FHIT-mediated MDM2 inactivation and p53 stabilization in human non-small cell lung cancer cells.

Aberrations of the tumor suppressor genes FHIT and p53 are frequently associated with a wide range of human cancers, including lung cancer. We studied the combined effects of FHIT and p53 proteins on tumor cell proliferation and apoptosis in human non-small cell lung carcinoma (NSCLC) cells in vitro and on tumor growth in animal models by adenoviral vector-mediated cotransfer of wild-type FHIT and p53 genes. We found that the coexpression of FHIT and p53 synergistically inhibited tumor cell proliferation in NSCLC cells in vitro and suppressed the growth of human tumor xenografts in nude mice.

5-aza-2'-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells.

Treating lung cancer cell lines using low-dose 5-aza-2'-deoxycytidine (DAC) caused an accumulation of procaspase-9 through mRNA upregulation, but the cells did not undergo apoptosis. However, when cells were treated with DAC and infected with a low dose of a recombinant wild-type p53 adenovirus vector (Ad-p53), a synergistic growth inhibitory effect was observed. Combination treatment induced Apaf-1 and procaspase-9 expression in which cytochrome c releases by Ad-p53 triggered the mitochondrial pathway of apoptosis.

Expression of constitutively activated EGFRvIII in non-small cell lung cancer.

The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvIII, de2-7 EGFR or deltaEGFR) has an in-frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvIII has been reported to be tumor-specific and has oncogenic potential, it is being investigated as a potential therapeutic target. Because the cell-specific expression of EGFRvIII in lung has not been well documented, we examined the expression of EGFRvIII in 76 non-small cell lung cancers (NSCLCs) and 10 non-neoplastic lung tissues by immunohistochemistry using a new monoclonal antibody specific for this variant receptor.

The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells.

Microtubules have a critical role in cell division, and consequently various microtubule inhibitors have been developed as anticancer drugs. In this study, we assess mebendazole (MZ), a microtubule-disrupting anthelmintic that exhibits a potent antitumor property both in vitro and in vivo. Treatment of lung cancer cell lines with MZ caused mitotic arrest, followed by apoptotic cell death with the feature of caspase activation and cytochrome c release.

Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo.

We have found that mebendazole (MZ), a derivative of benzimidazole, induces a dose- and time-dependent apoptotic response in human lung cancer cell lines. In this study, MZ arrested cells at the G(2)-M phase before the onset of apoptosis, as detected by using fluorescence-activated cell sorter analysis. MZ treatment also resulted in mitochondrial cytochrome c release, followed by apoptotic cell death.