To establish a genetic susceptibility assessment model of lung cancer risk potentially associated with polycyclic aromatic hydrocarbon (PAH) inhalation exposure among non-smokers in China, a total of 143 patients with lung adenocarcinoma and 143 cancer-free individuals were recruited. Sixty-eight genetic polymorphisms in 10 pathways related to PAH metabolism and tumorigenesis were selected and examined. It was observed that 3 genetic polymorphisms, along with 10 additional genetic polymorphisms via gene-gene interactions, significantly influenced lung cancer risk potentially associated with PAH inhalation exposure. Most polymorphisms were associated with PAH metabolism. According to the established genetic susceptibility score (GSS), lung cancer risk increased with a rise in the GSS level, thereby indicating a positive dose-response relationship.
Adenocarcinoma ; chemically induced ; epidemiology ; genetics ; Air Pollutants ; toxicity ; China ; Genetic Predisposition to Disease ; Humans ; Inhalation Exposure ; Lung Neoplasms ; chemically induced ; epidemiology ; genetics ; Polycyclic Aromatic Hydrocarbons ; toxicity

OBJECTIVETo study the alteration of circulating microRNAs in 4-(methylnitrosamino)-1-(3-pyridyl) -1-butanone (NNK)-induced early stage lung carcinogenesis.

METHODSA lung cancer model of male F344 rats was induced with systemic NNK and levels of 8 lung cancer-associated miRNAs in whole blood and serum of rats were measured by quantitative RT-PCR of each at weeks 1, 5, 10, and 20 following NNK treatment.

RESULTSNo lung cancer was detected in control group and NNK treatment group at week 20 following NNK treatment. The levels of some circulating miRNAs were significantly higher in NNK treatment group than in control group. The miR-210 was down-regulated and the miR-206 was up-regulated in NNK treatment group. The expression level of circulating miRNAs changed from week 1 to week 20 following NNK treatment.

CONCLUSIONThe expression level of circulating miRNAs is related to NNK-induced early stage lung carcinogenesis in rats and can therefore serve as its potential indicator.

Adenocarcinoma ; chemically induced ; Animals ; Carcinogenesis ; Cell Line, Tumor ; Gene Expression Regulation ; physiology ; Humans ; Lung ; drug effects ; pathology ; Lung Neoplasms ; blood ; chemically induced ; metabolism ; Male ; MicroRNAs ; blood ; genetics ; metabolism ; Nitrosamines ; pharmacology ; Rats ; Rats, Inbred F344

The effective and toxic ranges of anticancer drugs are very narrow and, in some cases, inverted. Thus determination of the most appropriate dosage and schedule of administration is crucial for optimal chemotherapy. In common arm trials conducted in Japan and by Southwest Oncology Group (SWOG) that used the same doses and schedules for the administration of carboplatin plus paclitaxel, the frequency of hematological toxicity was significantly higher in the Japanese trials than in the SWOG trial, despite demonstrating similar response rates. The frequency of epidermal growth factor receptor (EGFR) mutations in tumors was significantly higher among East Asian populations, and these populations are also reported to demonstrate a higher response rates to epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs). The prevalence of interstitial lung disease induced by treatment with EGFR-TKIs has been shown to be quite high in the Japanese population. Clinical trials of cetuximab against non-small cell lung cancer and of bevacizumab against stomach cancer have shown that these agents are only active in Caucasians. In a trial examining the use of sorafenib after transarterial chemoembolization in Korean and Japanese patients with advanced hepatocellular carcinoma, the compliance and dose intensity of the drug were quite low compared with other trials. Although not only identified pharmacogenomics differences but also differences in social environment, and regional medical care, including pharmacoeconomics strongly influence ethnic differences in treatment response, further identification and understanding of the pharmacogenomics underlying ethnic differences will be essential to timely and reliable global development of new anticancer drugs.
Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use ; Asian Continental Ancestry Group ; Carcinoma, Non-Small-Cell Lung/drug therapy/ethnology ; Chemoembolization, Therapeutic ; Clinical Trials as Topic ; Drug Design ; Ethnic Groups ; Humans ; Japan ; Lung Diseases, Interstitial/chemically induced ; Lung Neoplasms/drug therapy/ethnology ; Mutation ; Pharmacogenetics/*methods ; Receptor, Epidermal Growth Factor/genetics ; Republic of Korea

OBJECTIVETo explore the efficacy and side effects of icotinib hydrochloride in the treatment of patients with advanced non-small cell lung cancer (NSCLC).

METHODSThe efficacy and side effects of icotinib hydrochloride in treatment of 59 cases with stage IV NSCIC and followed-up from March 2009 to January 2012 were retrospectively analyzed.

RESULTSTwenty seven patients (45.8%) showed partial response (PR), 17 patients (28.8%) achieved SD, and 15 (25.4%) had progressive disease. The objective response rate (ORR) was 45.8% (27/59), and disease control rate (DCR) was 74.6% (44/59). Among the 23 patients with EGFR mutation, ORR was 73.9% (17/23), and DCR was 95.7% (22/23). Thirty six patients (61.0%) achieved remission of symptoms to varying degrees. The main symptoms relieved were cough, asthmatic suffocating, pain and hoarseness. The major adverse events were mild skin rash (35.6%) and diarrhea (15.3%). Others were dry skin, nausea and stomach problems. The efficacy of icotinib hydrochloride were related to the ECOG performance status, smoking history, EGFR mutation and rash significantly (P < 0.05).

CONCLUSIONSMonotherapy with icotinib hydrochloride is effective and tolerable for patients with advanced NSCLC, especially with EGFR mutation.

Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; pathology ; Crown Ethers ; adverse effects ; therapeutic use ; Diarrhea ; chemically induced ; Disease Progression ; Exanthema ; chemically induced ; Exons ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; pathology ; Male ; Middle Aged ; Mutation ; Neoplasm Staging ; Quinazolines ; adverse effects ; therapeutic use ; Receptor, Epidermal Growth Factor ; genetics ; Remission Induction ; Retrospective Studies ; Survival Rate

OBJECTIVETo investigate the effect of CYP1A1 and GSTM1 genetic polymorphisms and BPDE-DNA adducts on lung tumorigenesis.

METHODSThe case control study has included 200 cases of lung cancer and 200 controls. DNA was extracted from blood samples of all subjects. The genotype of both CYP1A1 and GSTM1 were detected with PCR-based restriction fragment length polymorphisms (PCR-RELP). BPDE-DNA adducts were detected with competitive ELISA.

RESULTSCYP1A1 mutant genotype and GSTM1 null genotype with smoke has increased the risk of lung cancer, with OR being 2.406(1.321-4.382), 2.755(1.470-5.163), respectively. The level of BPDE-DNA adducts in patients was greater than control, and the adduct level in ever smokers was higher than never smokers, the difference was statistically significant (P= 0.0252). GSTM1 null genotype individuals with BPDE-DNA level higher than 5 adducts/10(8) nucleotide have increased risk of lung cancer (OR= 1.988, 95%CI: 1.011-3.912). Compared with never smokers with CYP1A1 wild genotype, smokers with CYP1A1 mutation genotype had an increased risk of forming a higher level of DNA adducts (P= 0.0459). Smokers with GSTM1 null genotype formed more DNA adducts compared with never smokers with GSTM1 functional genotype (OR = 2.432, 95% CI: 1.072-4.517).

CONCLUSIONGSTM1 null genotype with higher level DNA adducts may increase the risk of lung cancer. DNA adducts form easier in smokers with CYP1A1 mutation genotype and GSTM1 null genotype, which in turn may influence lung tumorigenesis.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide ; Carcinogens ; Case-Control Studies ; Cytochrome P-450 CYP1A1 ; genetics ; DNA Adducts ; genetics ; Female ; Genotype ; Glutathione Transferase ; genetics ; Humans ; Lung Neoplasms ; chemically induced ; enzymology ; genetics ; Male ; Middle Aged ; Polymorphism, Genetic

OBJECTIVETo investigate the expression variation of RAR-β2, RASSF1A, and CDKN2A gene in the process of nickel-induced carcinogenesis.

METHODSNickel subsulfide (Ni(3)S(2)) at dose of 10 mg was given to Wistar rats by intramuscular injection. The mRNA expression of the three genes in induced tumors and their lung metastasis were examined by Real-time PCR. The methylation status of the 5' region of these genes were detected by Quantitative Real-time methylation specific PCR.

RESULTSThe mRNA expressions of the three genes both in muscle and lung tumor were decreased distinctly in comparison with normal tissue. But hypermethylation was found only in muscle tumor.

CONCLUSIONThese findings suggest that loss of function or decrease of RAR-β2, RASSF1A, and CDKN2A, as well as the hypermethylation of 5' region of these genes, are related with nickel exposure.

Animals ; Carcinogens ; toxicity ; CpG Islands ; Cyclin-Dependent Kinase Inhibitor p16 ; genetics ; metabolism ; DNA Methylation ; Gene Expression Regulation, Neoplastic ; drug effects ; Lung Neoplasms ; chemically induced ; metabolism ; Male ; Muscle Neoplasms ; chemically induced ; metabolism ; Nickel ; toxicity ; Rats ; Rats, Wistar ; Receptors, Retinoic Acid ; genetics ; metabolism ; Tumor Suppressor Proteins ; genetics ; metabolism

OBJECTIVETo investigate the expression and gene mutation of cluster of differentiation 9 (CD9) in the pathway of the mineral powder induced malignant transformation in immortalized human bronchial epithelial cells (BEAS-2B) in Gejiu.

METHODSBEAS-2B cells served as the control group and its malignant transformation cells induced by mineral powder in Gejiu were considered as experiment group. The expression of CD9 protein in 20 bottles of BEAS-2B cells and 20 bottles of malignant transformation cells was evaluated by immunocytochemistry. The mRNA expression of CD9 in 10 bottles of BEAS-2B cells and 10 bottles of malignant transformation cells was examined by reverse transcriptase polymerase chain reaction (RT-PCR). Gene mutation was detected in the products of RT-PCR by DNA sequencing.

RESULTSThere was significant difference between the expression of CD9 protein in BEAS-2B cells (100%, 20/20) and that in its malignant transformation cells (35%, 7/20 P < 0.01). The expression of CD9 mRNA in BEAS-2B cells 0.91 +/- 0.09 was significantly higher than that in its malignant transformation cells (0.34 +/- 0.14) (P < 0.01). Two point mutation of CD9 gene was detected in the malignant transformation cells of BEAS-2B by DNA sequencing. The change of G-->T in the base of 231 led to the change of Gln-->His in the amino acids of 40. The change of T-->A in the base of 119 led to the change of Val-->Asp in the amino acids of 3.

CONCLUSIONThe absence or down-regulation of CD9 expression and point mutation in the malignant transformation cells of BEAS-2B may play a considerable role in the pathway of the malignant transformation in the BEAS-2B cells induced by mineral powder in Gejiu.

Bronchi ; pathology ; Cell Line ; Cell Transformation, Neoplastic ; drug effects ; genetics ; Dust ; Epithelial Cells ; drug effects ; metabolism ; pathology ; Gene Expression Regulation ; drug effects ; Humans ; Lung Neoplasms ; chemically induced ; genetics ; metabolism ; pathology ; Mining ; Mutation ; drug effects ; Tetraspanin-29 ; genetics ; metabolism

OBJECTIVETo compare the asbestos-induced DNA damage and repair capacities of DNA damage between 104 asbestos-exposed workers and 101 control workers in Qingdao City of China and to investigate the possible association between polymorphisms in codon 399 of XRCC1 and susceptibility to asbestosis.

METHODSDNA damage levels in peripheral blood lymphocytes were determined by comet assay, and XRCC1 genetic polymorphisms of DNA samples from 51 asbestosis cases and 53 non-asbestosis workers with a similar asbestos exposure history were analyzed by PCR/RFLP.

RESULTSThe basal comet scores (3.95 +/- 2.95) were significantly higher in asbestos-exposed workers than in control workers (0.10 +/- 0.28). After 1 h H2O2 stimulation, DNA damage of lymphocytes exhibited different increases. After a 4 h repair period, the comet scores were 50.98 +/- 19.53 in asbestos-exposed workers and 18.32 +/- 12.04 in controls. The residual DNA damage (RD) was significantly greater (P<0.01) in asbestos-exposed workers (35.62%) than in controls (27.75%). XRCC1 genetic polymorphism in 104 asbestos-exposed workers was not associated with increased risk of asbestosis. But compared with polymorphisms in the DNA repair gene XRCC1 (polymorphisms in codon 399) and the DNA damage induced by asbestos, the comet scores in asbestosis cases with Gln/Gln, Gln/Arg, and Arg/Arg were 40.26 +/- 18.94, 38.03 +/- 28.22, and 32.01 +/- 11.65, respectively, which were higher than those in non-asbestosis workers with the same genotypes (25.58 +/- 11.08, 37.08 +/- 14.74, and 29.38 +/- 10.15). There were significant differences in the comet scores between asbestosis cases and non-asbestosis workers with Gln/Gln by Student's t-test (P<0.05 or 0.01). The comet scores were higher in asbestosis workers with Gln/Gln than in those with Arg/Arg and in non-asbestosis workers exposed to asbestos, but without statistically significant difference.

CONCLUSIONSExposure to asbestos may be related to DNA damage or the capacity of cells to repair H2O2-induced DNA damage. DNA repair gene XRCC1 codon 399 may be responsible for the inter-individual susceptibility in DNA damage and repair capacities.

Adult ; Aged ; Amino Acid Substitution ; Arginine ; blood ; Asbestos ; toxicity ; Comet Assay ; DNA Damage ; drug effects ; genetics ; DNA Repair ; drug effects ; genetics ; DNA-Binding Proteins ; genetics ; Genotype ; Glutamine ; blood ; Humans ; Hydrogen Peroxide ; toxicity ; Lung Neoplasms ; chemically induced ; genetics ; Lymphocytes ; metabolism ; Middle Aged ; Occupational Exposure ; Polymerase Chain Reaction ; Polymorphism, Genetic ; drug effects ; physiology ; X-ray Repair Cross Complementing Protein 1

OBJECTIVETo investigate the effectiveness and safety of domestically produced recombinant human interleukin 11 (rhIL-11) for the treatment of chemotherapy- induced thrombocytopenia.

METHODSA total of 32 solid cancer patients who developed chemotherapy-induced thrombocytopenia ( _70 x 10(9)/L) after the first cycle of chemotherapy was studied by self-cross control. The patients were given subcutaneous injection of rhIL-11 (25 microg x kg(-1) x d(-1)) for 7 to 14 consecutive days or until platelet count > or = 100 x 10(9)/L during the second cycle of chemotherapy using the identical regimen as in the first cycle.

RESULTSThe mean platelet count of the patients after rhIL-11 treatment was higher at different time points during the second cycle of chemotherapy than that during the first cycle of chemotherapy with the mean platelet count of (110.2 +/- 53.5) x 10(9)/L in the first cycle of chemotherapy versus (55.6 +/- 46.8) x 10(9)/L in the second cycle of chemotherapy (P < 0. 01). Patients with platelet count < or = 50 x 10(9)/L was 4/32 (12.5%) in the first cycle of chemotherapy and 12/32 (37.5%) in the second cycle of chemotherapy (P < 0.01). The time recovery to the normal platelet count was 2 - 18 days (median 5 days) in the first cycle of chemotherapy versus 5 - 27 days (median 12 days) in the second cycle of chemotherapy (P < 0.01). The case/frequency of the platelet transfusion was 2/2 in the first cycle of chemotherapy, while it was 7/9 in the second cycle of chemotherapy (P < 0.01). The major adverse reactions relative to rhIL-11 treatment were fatigue, myalgia/arthralgia, ache, headache, palpitation, edema and fever, most of which could be relieved automatically without any specific treament. However, some 3 grade side effects such as fatigue, myalgia/arthralgia and headache needed proper medication.

CONCLUSIONrhIL-11 is safe and effective for chemotherapy-induced thrombocytopenia with mild and manageable side effects.

Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Breast Neoplasms ; drug therapy ; Carboplatin ; administration & dosage ; Fatigue ; chemically induced ; Female ; Humans ; Injections, Subcutaneous ; Interleukin-11 ; adverse effects ; genetics ; therapeutic use ; Lung Neoplasms ; drug therapy ; Male ; Middle Aged ; Paclitaxel ; administration & dosage ; Platelet Count ; Recombinant Proteins ; administration & dosage ; adverse effects ; therapeutic use ; Stomach Neoplasms ; drug therapy ; Thrombocytopenia ; chemically induced ; drug therapy ; Treatment Outcome

OBJECTIVETo investigate the roles of p53 and K-ras gene in carcinogenesis and development of the lung carcinoma induced by 3-methylcholanthrene (MCA) and diethylinitrosamine (DEN) in Wistar rats, and to elucidate the relationships between the protein expression and gene mutation of p53 and K-ras.

METHODSMicrodissection was used to obtain pure cell populations of each phase in the carcinogenesis and development of lung carcinoma induced by MCA and DEN. DNA of the microdissected cell populations was extracted and used to analyze the mutations of p53 exons 5 approximately 8 and K-ras exons 1 approximately 2 by PCR-SSCP. The expressions of p53 and K-ras protein in each phase were detected by immunohistochemistry.

RESULTSNo mutation and protein expression of p53 and K-ras was found in the 30 cases with normal bronchial epithelium. Mutation of p53 was detected in 3.1% of 18 hyperplasia and 14 squamous metaplasia cases, 28.6% of 21 dysplasia, 30.0% of 12 carcinomas in situ, 51.2% of 43 infiltration carcinomas, 52.9% of 17 metastases. The positive immunostaining rate of p53 protein was 0, 42.9%, 50.0%, 60.5% and 64.7% respectively. K-ras mutation rate was 0, 4.8%, 8.3%, 9.3%, 11.8% respectively, while the overexpression rate of K-ras protein was 15.6%, 19.0%, 25.0%, 41.9%, 52.9% respectively. p53 protein expression was closely related with p53 mutation (P < 0.005, Pearson's R = 0.599 6). There was no relationship between the protein expression and gene mutation of K-ras (P > 0.500).

CONCLUSIONSp53 gene mutation and K-ras overexpression were early events in the carcinogenesis and development of rat lung carcinoma induced by MCA and DEN, while K-ras mutation does not play any important role.

Animals ; Genes, p53 ; Genes, ras ; Humans ; Immunohistochemistry ; Lung Neoplasms ; chemically induced ; chemistry ; genetics ; Mice ; Mutation ; Polymerase Chain Reaction ; Polymorphism, Single-Stranded Conformational ; Rats ; Tumor Suppressor Protein p53 ; analysis ; ras Proteins ; analysis