Biomedical subjects

Hideo Kunitoh

Publications and source records attributed to Hideo Kunitoh.

At least 19 recordsLinked to original sources

PubMed2025

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

East Asian never smokers↗

PubMed2006

Pharmacokinetics and pharmacodynamics of weekly epoetin beta in lung cancer patients.

BACKGROUND: To assess the pharmacokinetic profile and time-course of trough concentrations and hemoglobin levels associated with subcutaneous weekly administration of epoetin beta in lung cancer patients with chemotherapy-induced anemia. METHODS: Epoetin beta was subcutaneously administered to 15 anemic lung cancer patients once weekly for 8 weeks at doses of 9000, 18,000 and 36,000 IU. Pharmacokinetic parameters (C(max), AUC(inf) and T(1/2)) were determined after the first single dose administration on a model-independent basis, and the relationship between the dose and these parameters was examined for linearity. RESULTS: Weekly administration of epoetin beta at 9000, 18,000 and 36,000 IU produced C(max) values of 308 +/- 117 (mean +/- standard deviation), 678 +/- 86.7 and 1316 +/- 766 mIU/ml, and AUC(inf) values of 15,300 +/- 9524, 54,574 +/- 16,265 and 88,501 +/- 55,687 hr mIU/ml, respectively, showing dose-proportional increases. Trough concentrations tended to increase in the presence of severe bone marrow suppression induced by chemotherapy or other factors. Extremely high values were seen in three patients, but there was no apparent trend toward an increase with repeated doses. After 8 weeks' administration at 9000, 18,000 and 36,000 IU, hemoglobin levels were changed by -0.37 +/- 1.26, 2.15 +/- 1.36 and 2.82 +/- 2.17 g/dl, respectively. CONCLUSIONS: Epoetin beta exhibited linear pharmacokinetics when administered to anemic cancer patients at weekly doses of 9000-36,000 IU and did not cause drug accumulation. Hemoglobin levels increased with weekly doses of 18,000 or 36,000 IU.

Adenocarcinoma↗

PubMed2006

Impact of the haplotype CYP3A4*16B harboring the Thr185Ser substitution on paclitaxel metabolism in Japanese patients with cancer.

OBJECTIVE: Paclitaxel is one of the most important anticancer drugs for the treatment of various tumors such as non-small cell lung cancer. We investigated the association between CYP3A4 haplotypes and pharmacokinetic parameters of paclitaxel metabolism. METHODS: This study enrolled 235 Japanese patients with cancer who were receiving paclitaxel. These patients were screened for CYP3A4 gene polymorphisms by either direct sequencing or pyrosequencing. Plasma concentrations of paclitaxel and its 3 metabolites were determined by HPLC in 229 patients. RESULTS: Median values of paclitaxel clearance, normalized for body surface area, were lower in the high-dose group (>or=175 mg/m2, n = 199) than in the low-dose group (<or=100 mg/m2, n = 30), suggesting nonlinearity of pharmacokinetics caused by Cremophor EL. Therefore we mainly used the patients in the high-dose group for further analysis. The median value of the area under the curve (AUC) ratio of 3'-p-hydroxypaclitaxel to paclitaxel was 20% greater (95% confidence interval, 2.4% to 41.7%) in the women than in the men (P = .01). Although no significant difference in paclitaxel clearance was observed among the CYP3A4 haplotypes, 16B-bearing (1/16B) patients (n = 8) showed a 20% lower (95% confidence interval, -58.5 to -11.5%) median AUC ratio of 3'-p-hydroxypaclitaxel to paclitaxel (P = .04) and a 2.4-fold higher median AUC ratio of 6alpha-hydroxypaclitaxel to paclitaxel (P < .001) compaed with those in the wild-type (1/1) patients (n = 180). In contrast, no significant differences were seen between 1/1 and 18B/1 (n = 10) patients for the pharmacokinetic parameters examined. CONCLUSIONS: Our results suggest that CYP3A416B is associated with both reduced 3'-p-hydroxylation of paclitaxel and probably increased levels of 6alpha-hydroxypaclitaxel.

Adult↗

PubMed2006

Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients.

PURPOSE: To disclose characteristics of lung cancer patients developing radiation-induced lung injury treated with or without corticosteroid therapy. METHODS AND MATERIALS: Radiographic changes, symptoms, history of corticosteroid prescription, and clinical course after 50-70 Gy of thoracic radiotherapy were retrospectively evaluated in 385 lung cancer patients. RESULTS: Radiation-induced lung injury was stable without corticosteroid in 307 patients (Group 1), stable with corticosteroid in 64 patients (Group 2), and progressive to death despite corticosteroid in 14 patients (Group 3). Fever and dyspnea were noted in 11%, 50% and 86% (p<0.001), and in 13%, 44% and 57% (p<0.001) patients in Groups 1-3, respectively. Median weeks between the end of radiotherapy and the first radiographic change were 9.9, 6.7 and 2.4 for Groups 1-3, respectively (p<0.001). The initial prednisolone equivalent dose was 30-40 mg daily in 52 (67%) patients. A total of 16 (4.2%) patients died of radiation pneumonitis or steroid complication with a median survival of 45 (range, 8-107) days. CONCLUSION: Development of fever and dyspnea, and short interval between the end of radiotherapy and the first radiographic change were associated with fatal radiation-induced lung injury. Prednisolone 30-40 mg daily was selected for the treatment in many patients.

Adrenal Cortex Hormones↗

PubMed2006

Detection of epidermal growth factor receptor mutations in serum as a predictor of the response to gefitinib in patients with non-small-cell lung cancer.

Cases of non-small-cell lung cancer (NSCLC) carrying the somatic mutation of epidermal growth factor receptor (EGFR) have been shown to be hyperresponsive to the EGFR tyrosine kinase inhibitor gefitinib (IRESSA). If EGFR mutations can be observed in serum DNA, this could serve as a noninvasive source of information on the genotype of the original tumor cells that could influence treatment and the ability to predict patient response to gefitinib. Serum genomic DNA was obtained from Japanese patients with NSCLC before first-line gefitinib monotherapy. Scorpion Amplified Refractory Mutation System technology was used to detect EGFR mutations. Wild-type EGFR was detected in all of the 27 serum samples. EGFR mutations were detected in 13 of 27 (48.1%) patients and two major EGFR mutations were identified (E746_A750del and L858R). The EGFR mutations were seen significantly more frequently in patients with a partial response than in patients with stable disease or progressive disease (P = 0.046, Fisher's exact test). The median progression-free survival was significantly longer in patients with EGFR mutations than in patients without EGFR mutations (200 versus 46 days; P = 0.005, log-rank test). The median survival was 611 days in patients with EGFR mutations and 232 days in patients without EGFR mutations (P > 0.05). In pairs of tumor and serum samples obtained from 11 patients, the EGFR mutation status in the tumors was consistent with those in the serum of 8 of 11 (72.7%) of the paired samples. Thus, EGFR mutations were detectable using Scorpion Amplified Refractory Mutation System technology in serum DNA from patients with NSCLC. These results suggest that patients with EGFR mutations seem to have better outcomes with gefitinib treatment, in terms of progression-free survival, overall survival, and response, than those patients without EGFR mutations.

Adult↗

PubMed2006

Association of the OGG1-Ser326Cys polymorphism with lung adenocarcinoma risk.

Adenocarcinoma (ADC) is the most frequent histological type of lung cancer and comprises the majority of lung cancers in non-smokers. Thus, genetic factors responsible for ADC susceptibility need to be determined to establish efficient ways of preventing the disease. The OGG1 gene, encoding a glycosylase for 8-hydroxyguanine, an oxidatively damaged promutagenic base, has the polymorphism Ser326Cys, and OGG1-326Cys protein was indicated to have a lower ability to prevent mutagenesis than the OGG1-326Ser protein. Case-control studies to date suggest that the OGG1-326Cys allele is associated with a higher risk for several types of cancers, including overall lung cancer. However, the contribution of this polymorphism to lung ADC risk is unclear. In the present study, the OGG1-Ser326Cys polymorphism was assessed for association with lung ADC risk using a case-control study of a Japanese population consisting of 1097 cases and 394 controls. Odds ratios (OR) of the 326Cys allele carriers increased in a dose-dependent manner with allele number (P for the trend test = 0.04). The OR of homozygotes for the 326Cys allele was increased significantly when homozygotes for the 326Ser allele were used as a reference (OR = 1.5, 95% confidence interval [CI] = 1.0-2.1, P = 0.04). Furthermore, the overall OR for lung ADC of the Cys/Cys homozygotes out of a total of 1925 ADC patients and 3449 controls from six case-control studies reported up to the present were 1.43 (95% CI = 1.11-1.84, P = 0.0045). These results indicate that OGG1-326Cys functions as a risk allele for lung ADC development.

Adenocarcinoma↗

PubMed2006

Common arm analysis: one approach to develop the basis for global standardization in clinical trials of non-small cell lung cancer.

The global development of new anticancer treatments is desirable. However, whether results of clinical trials performed in one population can be fully extrapolated to another population remains in question. We retrospectively compared "common arms" of platinum-based doublet phase III trials among Japanese, European, and American patients with non-small cell lung cancer to develop the basis for global standardization in clinical trials. Patient demographics were very similar through all studies, indicating that extrinsic ethnic factors including socioeconomic factors, medical service background, and patient selection process for clinical trials may be consistent between geographically different oncology groups. The doses of docetaxel, gemcitabine, and vinorelbine were lower in Japanese studies. The toxicity profile was generally acceptable and similar among many studies. Thus, the dose and schedule of anticancer agents established in prior phase I and II studies conducted in each country were appropriate and applicable to large patient populations in these countries. Response rates seemed to be distributed randomly from one study to another, whereas patient survival might be better in Japanese studies. In conclusion, geographical differences in the dose of anticancer agents, response, survival and toxicity of lung cancer chemotherapy were actually observed. However, extrapolation of clinical data obtained in one country to another population and global clinical trials were considered possible with adequate dose adjustment based on dose finding studies using a carefully projected protocol.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk.

Fifty single-nucleotide polymorphisms (SNPs) associated with amino acid changes in 36 genes involved in diverse DNA repair pathways were assessed for associations with risk for small cell lung carcinoma (SCLC) by a case-control study consisting of 211 SCLC cases and 685 controls. An SNP, Val83Met, in the MTH1 (microtT homolog 1) gene encoding a triphosphatase that hydrolyzes pro-mutagenic oxidized nucleoside triphosphates, such as 8-hydroxy-dGTP and 2-hydroxy-dATP, showed the strongest and a significant association with SCLC risk [odds ratio (OR)=1.6, 95% confidence interval (CI): 1.2-2.2, P=0.004], while three other SNPs in the TP53, BLM and SNM1 genes, respectively, also showed marginal associations (0.05<P<0.1). Another SNP, which causes a nucleotide change in the 5'-UTR of MTH1 transcripts leading to alternative translation initiation, was additionally examined and the SNP also showed a significant association (OR=1.7, 95% CI: 1.2-2.3, P=0.002). The two SNPs in the MTH1 gene were in linkage disequilibrium, and the OR for carrying a copy of the haplotype consisting of both the risky SNP alleles was 2.0 (95% CI: 1.2-3.2, P=0.002). The present results indicate that inter-individual differences in MTH1 activities due to SNPs are involved in susceptibility to SCLC.

Adult↗

PubMed2006

Small-cell lung cancer with lymphadenopathy in an 18-year-old female nonsmoker.

BACKGROUND: An asymptomatic 18-year-old female presented in December 2002 with a left pulmonary mass, and an enlarged mediastinum and left hilum, detected on a routine chest X-ray. She had never smoked, and had no history of exposure to known carcinogens, no history of serious illnesses and no family history of malignancy. Superficial lymph nodes were not palpable. A CT scan of the chest disclosed a round tumor in the left lower lobe and marked enlargement of the ipsilateral hilar and mediastinal lymph nodes. INVESTIGATIONS: CT scan of the chest, routine hematological study, sputum smear and culture for acid-fast bacilli, transbronchial lung biopsy, serum tumor markers, CT scan of the abdomen, MRI scan of the head, bone scintigraphy, lung function tests, blood gas analysis, pathological examination including hematoxylin-eosin staining and immunohistochemistry using chromogranin A, CD56 (neural cell adhesion molecule), and cytokeratin antibodies. DIAGNOSIS: Limited-stage small-cell lung cancer (T1N2M0, clinical stage IIIA). MANAGEMENT: Etoposide plus cisplatin chemotherapy with concurrent accelerated hyperfractionated thoracic radiotherapy, left pneumonectomy and lymph-node dissection.

Adolescent↗

PubMed2006

Effect of the introduction of minimum lesion size on interobserver reproducibility using RECIST guidelines in non-small cell lung cancer patients.

We evaluated interobserver reproducibility for the response evaluation criteria in solid tumors (RECIST) guidelines and the influence of minimum lesion size (MLS) on reproducibility. The 110 consecutive patients with non-small cell lung cancer were treated with platinum-based chemotherapy. Five observers measured target lesions according to both the World Health Organization (WHO) criteria and RECIST. The percentage changes for unidimensional measurements (UD; RECIST type) and bidimensional measurements (BD; WHO type) were calculated for each patient. Interobserver reproducibility among five observers, that is 10 pairs, was expressed as the Spearman's correlation coefficient for the percentage changes, the proportion of agreement and the kappa statistics for response categories. The same analysis was carried out using MLS. BD was more reproducible than UD (Spearman rank correlation coefficient, 0.84 vs 0.81; proportion of agreement, 84.4% vs 82.5%; kappa value, 0.69 vs 0.61). When MLS was applied to UD, eligible cases decreased by 6.4% and the number of target lesions by 44.6%, whereas interobserver reproducibility for UD improved (Spearman rank correlation coefficient, 0.81-0.84; proportion of agreement, 82.5-84.2%; kappa value, 0.61-0.65). The introduction of MLS to UD could also improve intercriteria reproducibility between WHO and RECIST. It is important to apply the MLS when using RECIST for the comparable interobserver reproducibility attained with WHO.

Adult↗

PubMed2006

High sensitivity detection of epidermal growth factor receptor mutations in the pleural effusion of non-small cell lung cancer patients.

Epidermal growth factor receptor (EGFR) mutations are a strong determinant of tumor response to gefitinib in non-small cell lung cancer (NSCLC). We attempted to elucidate the feasibility of EGFR mutation detection in cells of pleural effusion fluid. We obtained 24 samples of pleural effusion fluid from NSCLC patients. The pleural effusion fluid was centrifuged, and the cellular components obtained were used for detection. EGFR mutation status was determined by a direct sequencing method (exons 18-21) and by the Scorpion Amplified Refractory Mutation System (ARMS) method. EGFR mutations were detected in eight cases. Three mutations were detected by both methods, and the other five mutations were detected by Scorpion ARMS alone. The mutations were detected by both methods in all four partial responders among the seven patients who received gefitinib therapy. Direct sequencing detected the mutations in only two of four cases with partial response. These results suggest that the DNA in pleural effusion fluid can be used to detect EGFR mutations. The Scorpion ARMS method appears to be more sensitive for detecting EGFR mutations than the direct sequencing method.

Adult↗

PubMed2006

Genetic variation and haplotype structure of the ABC transporter gene ABCG2 in a Japanese population.

The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCG2, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of ABCG2 from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5'-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in ABCG2 and pharmacokinetic/pharmacodynamic parameters.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk.

Analyzing the CYP2A6 gene of subjects who showed a poor metabolic phenotype toward SM-12502, we discovered a novel mutant allele (CYP2A6*4C) lacking the whole CYP2A6 gene. Using genetically engineered Salmonella typhimurium expressing a human CYP, we found that CYP2A6 was involved in the metabolic activation of a variety of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contained in tobacco smoke. Taking these results into consideration, we hypothesized that the subjects carrying the CYP2A6*4C allele had lower risk of tobacco-related lung cancer. In accordance with our hypothesis, our epidemiological studies indicated that smokers homozygous for the CYP2A6*4C allele showed much lower odds ratios toward cancer risk. Other mutant alleles reducing the CYP2A6 activity, besides CYP2A6*4C, also reduced the risk of lung cancer in smokers, particularly of squamous-cell carcinoma and small-cell carcinoma, both smoking-related cancers. 8-Methoxypsoralen, an inhibitor of CYP2A6, efficiently prevented the occurrence of adenoma caused by NNK in A/J mice.

Animals↗

PubMed2005

Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer.

PURPOSE: To evaluate epidermal growth factor receptor (EGFR) mutations and copy number as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib. PATIENTS AND METHODS: Sixty-six patients with NSCLC who experienced relapse after surgery and received gefitinib were included. Direct sequencing of exons 18 to 24 of EGFR and exons 18 to 24 of ERBB2 was performed using DNA extracted from surgical specimens. Pyrosequencing and quantitative real-time polymerase chain reaction were performed to analyze the allelic pattern and copy number of EGFR. RESULTS: Thirty-nine patients (59%) had EGFR mutations; 20 patients had deletional mutations in exon 19, 17 patients had missense mutations (L858R) in exon 21, and two patients had missense mutations (G719S or G719C) in exon 18. No mutations were identified in ERBB2. Response rate (82% [32 of 39 patients] v 11% [three of 27 patients]; P < .0001), time to progression (TTP; median, 12.6 v 1.7 months; P < .0001), and overall survival (median, 20.4 v 6.9 months; P = .0001) were significantly better in patients with EGFR mutations than in patients with wild-type EGFR. Increased EGFR copy numbers (> or = 3/cell) were observed in 29 patients (44%) and were significantly associated with a higher response rate (72% [21 of 29 patients] v 38% [14 of 37 patients]; P = .005) and a longer TTP (median, 9.4 v 2.6 months; P = .038). High EGFR copy numbers (> or = 6/cell) were caused by selective amplification of mutant alleles. CONCLUSION: EGFR mutations and increased copy numbers were significantly associated with better clinical outcome in gefitinib-treated NSCLC patients.

Adult↗

PubMed2005

Functional analysis of four naturally occurring variants of human constitutive androstane receptor.

The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.

Animals↗

PubMed2005

Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk.

Single nucleotide polymorphisms (SNPs) were searched for in 36 genes involved in diverse DNA repair pathways, and 50 nonsynonymous (associated with amino acid changes) SNPs identified were assessed for associations with lung cancer risk by a case-control study consisting of 752 adenocarcinoma cases, 250 squamous cell carcinoma cases and 685 controls. An SNP, Arg72Pro, of the TP53 gene encoding a DNA damage response protein showed the strongest association with squamous cell carcinoma risk (OR Pro/Pro vs. Arg/Arg = 2.2), while 2 other SNPs, Phe257Ser of the REV gene encoding a translesion DNA polymerase and Ile658Val of the LIG4 gene encoding a DNA double-strand break repair protein, also showed associations (OR Ser/Ser vs. Phe/Phe = 2.0 and OR Ile/Val vs. Ile/Ile = 0.4, respectively). An SNP, Thr706Ala, in the POLI gene encoding another translesion DNA polymerase was associated with adenocarcinoma and squamous cell carcinoma risk, particularly in individuals of ages < 61 years (OR Ala/Ala + Ala/Thr vs. Thr/Thr = 1.5 and 2.4, respectively). POLI is the human counterpart of PolI, a strong candidate for the Par2 (pulmonary adenoma resistance 2) gene responsible for adenoma/adenocarcinoma susceptibility in mice. The present results suggest that these 4 SNPs function as genetic factors underlying lung cancer susceptibility by modulating activities to maintain the genome integrity of each individual.

Adenocarcinoma↗

PubMed2005

Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy.

BACKGROUND: The efficacy of chemotherapy in patients with large cell neuroendocrine carcinoma of the lung (LCNEC) remains unclear. METHODS: Patients with LCNEC who received cisplatin-based chemotherapy were identified by reviewing 567 autopsied and 2790 surgically resected lung cancer patients. The clinical characteristics and objective responses to chemotherapy in these patients were analyzed. RESULTS: Overall, 20 cases of LCNEC were identified, including stage IIIA (n=3), stage IIIB (n=6), stage IV (n=6) and postoperative recurrence (n=5) cases. Six patients had received prior chemotherapy, and 14 were chemo-naive patients. The patients had received a combination of cisplatin and etoposide (n=9), cisplatin, vindesine and mitomycin (n=6), cisplatin and vindesine (n=4), or cisplatin alone (n=1). One patient showed complete response and nine showed partial response, yielding an objective response rate of 50%. The response rate did not differ between patients with the initial diagnosis of SCLC and those with the initial diagnosis of NSCLC, however, the response rate in chemo-naive patients (64%) was significantly different from that in previously treated patients (17%). CONCLUSIONS: Our results suggest that the response rate of LCNEC to cisplatin-based chemotherapy was comparable to that of SCLC.

Adenocarcinoma↗

PubMed2005

Functional characterization of five novel CYP2C8 variants, G171S, R186X, R186G, K247R, and K383N, found in a Japanese population.

Cytochrome P450 2C8 is one of the primary enzymes responsible for the metabolism of a wide range of drugs such as paclitaxel, cerivastatin, and amiodarone. We have sequenced the CYP2C8 gene from 201 Japanese subjects and found five novel nonsynonymous single nucleotide polymorphisms (SNPs): 511G>A (G171S), 556C>T (R186X; X represents the translational stop codon), 556C>G (R186G), 740A>G (K247R), and 1149G>T (K383N), with the allele frequency of 0.0025. The CYP2C8 variants were heterologously expressed in COS-1 cells and functionally characterized in terms of expression level, paclitaxel 6alpha-hydroxylase activity, and intracellular localization. The prematurely terminated R186X variant was undetectable by Western blotting and inactive toward paclitaxel 6alpha-hydroxylation. The G171S, K247R, and K383N variants exhibited properties similar to those of the wild-type CYP2C8. Paclitaxel 6alpha-hydroxylase activity of the R186G transfectant was only 10 to 20% that of wild-type CYP2C8. Furthermore, the R186G variant displayed a lower level of protein expression in comparison to the wild type, which was restored by the addition of a proteasome inhibitor (MG-132; Z-Leu-Leu-Leu-aldehyde). The reduced CO-difference spectral analysis using recombinant proteins from an insect cell/baculovirus system revealed that the R186G variant has a minor peak at 420 nm in addition to the characteristic Soret peak at 450 nm, suggesting the existence of improperly folded protein. These results indicate that the novel CYP2C8 SNPs, 556C>T (R186X) and 556C>G (R186G), could influence the metabolism of CYP2C8 substrates such as paclitaxel and cerivastatin.

Animals↗