RRM1 gene expression in peripheral blood is predictive of shorter survival in Chinese patients with advanced non-small-cell lung cancer treated by gemcitabine and platinum

Objective  

To evaluate the predictive values of gene expressions of ribonucleotide reductase M1 (RRM1) and breast cancer susceptibility gene 1 (BRCA1) in peripheral blood from Chinese patients with non-small-cell lung cancer (NSCLC) treated with gemcitabine plus platinum.     

Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population

Objective:The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase(MTHFR) C677T excision repair cross-complementation group 1(ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer(NSCLC).Methods:A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens.The polymorphisms of MTHFR C677T,ERCC1 C8092A,and ERCC1 C118T were genotyped using the TaqMan methods.Results:The overall response rate was 28.9%.Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype(TT or CT)(41.2% versus 19.1%,P=0.01).Median time to progression(TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype(7.6 months versus 5.0 months,P=0.003).No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival.Conclusions:Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum.     

Inhibition of expression of vascular endothelial growth factor and its receptors in pulmonary adenocarcinoma cell by TNP-470 in combination with gemcitabine

Angiogenesis is required for solid tumor growth and facilitates tumor progression and metastasis. The inhibition effects of O-（chloroacetyl-carbamoyl） fumagillol （TNP-470）, an angiogenesis inhibitor, and gemcitabine, a chemotherapeutic agent, on expression of growth factors were investigated using human pulmonary adenocarcinoma cell line, A549. The A549 cells were divided into four groups： control group, 10^-6 mg/ml gemcitabine treated group, 10^-4 mg/ml TNP-470 treated group and gemcitabine＋TNP-470 treated group. The mRNA and protein expression of vascular endothelial growth factor （VEGF） and its receptors, FMS-like tyrosine kinase-l （FLT-1） and kinase insert domain-containing receptor （KDR）, in different groups were measured. The growth of A549 cell cultured with gemcitabine or TNP-470 was inhibited in an almost dose-dependent manner. Although gemcitabine （10^-6 mg/ml） alone and TNP-470 （10^-4 mg/ml） alone had no effect on the mRNA and protein expression of VEGF and its receptors （FLT-1, KDR） in A549 cells compared to the control （P〉0.05）, 10^-6 mg/ml gemcitabine in combination with 10^-4 mg/ml TNP-470 had significant effect （P〈0.01）. Moreover, combination of the two drugs significantly inhibited the mRNA expression of VEGF, FLT-1 and KDR compared to either drug alone （P〈0.05）. This study suggests that combined treatment with TNP-470 plus gemcitabine may augment the antiangiogenic and antineoplastic effects in lung cancer cells in vitro.     

Pharmacokinetics of gemcitabine in Chinese patients with non-small-cell lung cancer

INTRODUCTION Gemcitabine (2′,2′-difluorodeoxycytidine) is asynthetic pyrimidine nucleoside analogue with cyto-toxic activity in non-small-cell lung cancer (NSCLC)(Anderson et al., 1994; Abratt et al., 1994; Lund et al.,1994). Gemcitabine is a prodrug which, through de-oxycytidine kinase and other nucleotide kinases, ex-erts its cytotoxic effects through its active intracellu-lar metabolites, gemcitabine diphosphate andtriphosphate (Guchelaar et al., 1996;…     

Comparison of pharmacokinetics,efficacy and toxicity profile of gemcitabine using two different administration regimens in Chinese patients with non-small-cell lung cancer

Objective： To conduct a randomized comparative trial of pharmacokinetics, efficacy and toxicity profile treatment with 1200 mg/m^2 gemcitabine using standard 30-min infusion or fixed dose rate （FDR） infusion [10 mg/（m^2-min）] on days 1 and 8 plus carboplatin AUC （area under curve） 5 on day 1 in Chinese non-small-cell cancer patients. Twelve patients were enrolled in this study. Methods： Plasma gemcitabine concentrations were measured by ion-pair reversed phase high performance liquid chromatography. Antitumoral activity and toxicity of gemcitabine was assessed according to World Health Organization criteria. Results： The obtained mean parameters, such as T1/2 （elimination half time）, AUC, and CL （clearance）, were consistent with those reported in literature. Qualified response rate in our study was 33.3% for standard arm and 50% for FDR ann. Additional 50% and 33.3% patients contracted stable disease （SD） in standard arm and FDR arm, respectively. The predominant toxicity was hematologic, and patients in the standard infusion ann experienced consistently more hematologic toxicity, Conclusion： Pharmacokinetic and clinical data in this trial support the continued evaluation of the FDR infusion strategy with gemcitabine.