scholarly journals Intratumoral gene expression of dihydrofolate reductase and folylpoly-c-glutamate synthetase affects the sensitivity to 5-fluorouracil in non-small cell lung cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kayo Sakon ◽  
Masato Sasaki ◽  
Kaede Tanaka ◽  
Tae Mizunaga ◽  
Keita Yano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dihydrofolate Reductase ◽  
Antitumor Effect ◽  
Drug Sensitivity ◽  
Small Cell ◽  
Sensitivity Test ◽  
Small Cell Lung ◽  
Expression Levels ◽  
Drug Sensitivity Test ◽  
Glutamate Synthetase

Abstract Background Various factors related to the sensitivity of non-small cell lung carcinoma (NSCLC) to 5-fluorouracil (5-FU) have been reported, and some of them have been clinically applied. In this single-institutional prospective analysis, the mRNA expression level of five folic acid-associated enzymes was evaluated in surgical specimens of NSCLC. We investigated the correlation between the antitumor effect of 5-FU in NSCLC using an anticancer drug sensitivity test and the gene expression levels of five enzymes. Materials and methods Forty patients who underwent surgery for NSCLC were enrolled, and the antitumor effect was measured using an in vitro anticancer drug sensitivity test (histoculture drug response assay) using freshly resected specimens. In the same sample, the mRNA expression levels of five enzymes involved in the sensitivity to 5-FU were measured in the tumor using real-time PCR. The expression levels and the result of the sensitivity test were compared. Results No correlation was found between dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), or DPD/OPRT expression and the antitumor effects of 5-FU. On the other hand, a correlation was found between thymidylate synthase (TS), folylpoly-c-glutamate synthetase (FPGS), and dihydrofolate reductase (DHFR) expression and 5-FU sensitivity. Conclusion Expression of FPGS and DHFR may be useful for predicting the efficacy of 5-FU-based chemotherapy for NSCLC.

scholarly journals Intratumoral Gene Expression of Dihydrofolate Reductase and Folylpoly-C-Glutamate Synthetase Affects the Sensitivity to 5-Fluorouracil in Non-Small Cell Lung Cancer

2021 ◽  
Author(s):  
Kayo Sakon ◽  
Masato Sasaki ◽  
Kaede Tanaka ◽  
Tae Mizunaga ◽  
Keita Yano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dihydrofolate Reductase ◽  
Antitumor Effect ◽  
Drug Sensitivity ◽  
Small Cell ◽  
Sensitivity Test ◽  
Small Cell Lung ◽  
Expression Levels ◽  
Drug Sensitivity Test ◽  
Glutamate Synthetase

Abstract Background: Various factors related to the sensitivity of non-small cell lung carcinoma (NSCLC) to 5-fluorouracil (5-FU) have been reported, and some of them have been clinically applied. In this single-institutional prospective analysis, the mRNA expression level of five folic acid-associated enzymes was evaluated in surgical specimens of NSCLC. We investigated the correlation between the antitumor effect of 5-FU in NSCLC using an anticancer drug sensitivity test and the gene expression levels of five enzymes.Materials and Methods: Forty patients who underwent surgery for NSCLC were enrolled, and the antitumor effect was measured using an in vitro anticancer drug sensitivity test (histoculture drug response assay) using freshly resected specimens. In the same sample, the mRNA expression levels of five enzymes involved in the sensitivity to 5-FU were measured in the tumor using real-time PCR. The expression levels and the result of the sensitivity test were compared.Results: No correlation was found between dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), or DPD/OPRT expression and the antitumor effects of 5-FU. On the other hand, a correlation was found between thymidylate synthase (TS), folylpoly-c-glutamate synthetase (FPGS), and dihydrofolate reductase (DHFR) expression and 5-FU sensitivity.Conclusion: Expression of FPGS and DHFR may be useful for predicting the efficacy of 5-FU-based chemotherapy for NSCLC.

Verification of biomarkers in predicting drug sensitivity with in vitro 3D drug sensitivity test in non-small cell lung cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 11602-11602
Author(s):  
Dage Liu ◽  
Nariyasu Nakashima ◽  
Yoshuke Kita ◽  
Yoshimasa Tokunaga ◽  
Kazuhito Nii ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Sensitivity ◽  
Small Cell ◽  
Sensitivity Test ◽  
Small Cell Lung ◽  
Drug Sensitivity Test

scholarly journals Epigenetic Suppression of the T-box Subfamily 2 (TBX2) in Human Non-Small Cell Lung Cancer

2019 ◽  
Vol 20 (5) ◽  
pp. 1159 ◽  
Author(s):  
Eliana Nehme ◽  
Zahraa Rahal ◽  
Ansam Sinjab ◽  
Athar Khalil ◽  
Hassan Chami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung ◽  
Alveolar Cells ◽  
Expression Levels ◽  
Human Nsclc

(1) The TBX2 subfamily of transcription factors (TBXs 2, 3, 4 and 5) are markedly down-regulated in human non-small cell lung cancer (NSCLC) and exert tumor suppressor effects in lung malignancy. Yet, mechanisms underlying suppressed expression of the TBX2 subfamily in NSCLC are elusive. Here, we interrogated probable epigenetic mechanisms in suppressed expression of the TBX2 subfamily in human NSCLC. (2) TBX2 subfamily gene expression and methylation levels in NSCLC and normal lung tissues were surveyed using publicly available RNA-sequence and genome-wide methylation datasets. Methylation β-values of the four genes were statistically compared between NSCLCs and normal lung tissues, correlated with gene expression levels, and interrogated with clinicopathological variables. Expression and methylation levels of TBXs were quantified in NSCLC cells using real-time PCR and methylation-specific PCR assays, respectively. Effects of the DNA methyltransferase inhibitor 5-azacytidine (Aza) on TBX2 subfamily expression were assessed in NSCLC cells. Impact of TBX2 subfamily expression on Aza-treated cells was evaluated by RNA interference. (3) All four TBXs were significantly hypermethylated in NSCLCs relative to normal lung tissues (p < 0.05). Methylation β-values of the genes, with exception of TBX2, were significantly inversely correlated with corresponding mRNA expression levels (p < 0.05). We found no statistically significant differences in hypermethylation levels of the TBX2 subfamily by clinicopathological features including stage and tobacco history. Expression levels of the TBX genes were overall suppressed in NSCLC cells relative to normal alveolar cells. Members of the subfamily were significantly hypermethylated in all tested NSCLC cell lines relative to normal alveolar cells. Treatment with Aza induced the expression of the TBX2 subfamily concomitant with NSCLC cell growth inhibition. Further, simultaneous knockdown of the four TBX genes markedly reduced anti-growth effects of Aza in NSCLC cells. (4) Our study sheds light on new epigenetic profiles in the molecular pathogenesis of human NSCLC.

RRM1 expression is verified as a biomarker predicting the drug sensitivity for GEM with in vitro 3D drug sensitivity test in non-small cell lung cancer tumor.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20054-e20054
Author(s):  
Nariyasu Nakashima ◽  
Dage Liu ◽  
Takayuki Nakano ◽  
Yusuke Kita ◽  
Xia Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Predictive Value ◽  
Drug Sensitivity ◽  
Collagen Gel ◽  
Small Cell ◽  
Cancer Drug ◽  
Small Cell Lung ◽  
Drug Sensitivity Test ◽  
Anti Cancer

e20054 Background: Ribonucleotide reductase M1 (RRM1) is involved in regulation of cell proliferation and synthesis of deoxyribonucleotides for DNA. It is also a cellular target for gemcitabine (GEM) and overexpression of RRM1 was reported to be associated with the resistance to GEM. Though RRM1 expression has been reported as the biomarkers in predicting the response to chemotherapy clinically, the value of GEM remains inconsistent and controversial. Collagen gel droplet embedded culture-drug sensitivity test (CD-DST) is a newly developed in vitro chemosensitivity test that could directly inspect the anti-cancer drug sensitivity with fresh tumor tissue. With use of CD-DST test, we have verified the predictive value of RRM1 expression to the anti-cancer agent sensitivity for GEM in non-small cell lung cancer (NSCLC) tumor. Here, the predictive value of biomarker RRM1 to GEM was further verified with CD-DST. Methods: Twenty-five patients with primary NSCLC were used in this study. Expression of RRM1 was assessed by immunohistochemistry. For CD-DST test, viable cells were collected from fresh surgical specimen and embed into the collagen gel droplets in 3D condition. Tumor cells were exposed to GEM for 1 hour and further incubated with serum-free culture medium for 7 days. The in vitro sensitivity was expressed as the percentage T/C ratio, where T was the total volume of the treated group and C was the total volume of the control group. Results: 1)Anti-cancer drug sensitivity: The sensitivity for GEM (T/C%) was 76.2 ± 30.5. 2)Expression of biomarkers: RRM1 expression was 39.2 ± 28.2 %. 3) Correlation: The expression of RRM1 significantly correlated with drug sensitivity for GEM (r = 0.446, p = 0.0256). Higher expression of RRM1 indicated worse anti-cancer drug sensitivity for GEM. Conclusions: The significant correlation between the RRM1 expression and sensitivity to GEM was proved with CD-DST in NSCLC tumors. The expression of RRM1 may become a useful biomarker in predicting the drug sensitivity for GEM in NSCLC.

scholarly journals High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 273
Author(s):  
Vienna Ludovini ◽  
Fortunato Bianconi ◽  
Annamaria Siggillino ◽  
Jacopo Vannucci ◽  
Sara Baglivo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Early Stage ◽  
Small Cell ◽  
Small Cell Lung ◽  
Expression Levels ◽  
Immune Related Genes ◽  
Gene Expression Levels

Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression levels of immune-related genes PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ in tumor tissue of surgically resected NSCLC and correlated the finding with clinicopathological features and patient outcomes. A total of 191 consecutive early-stage NSCLC patients who underwent curative pulmonary resection were studied. The mRNA expression levels of immune-related genes were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Arrays (Qiagen). PD-1, PD-L2 and IDO-2 gene expression levels were significantly higher in patients with squamous histology (p = 0.001, p = 0.021 and p < 0.001; respectively). PD-1, PD-L1 and IDO-2 gene expression levels were significantly higher in patients with higher stage (p = 0.005, p = 0.048 and p = 0.002, respectively). The univariate analysis for recurrence-free survival (RFS) and overall survival (OS) showed that patients with higher levels of three-genes (PD-L1/PD-L2/INFγ) (hazard ratio (HR)) 1.90 (95% confidence interval (CI), 1.13–3.21), p = 0.015) were associated with a worse RFS, while patients with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS (HR 1.63 95% CI, 1.06–2.51, p = 0.024; HR 1.54 95% CI, 1.02–2.33, p = 0.04; respectively). The multivariate interaction model adjusted for histology and stage confirmed that higher levels of three genes (PD-L1/PD-L2/INFγ) were significantly associated with worse RFS (HR 1.98, p = 0.031) and higher levels of both genes (PD-L1/IDO-2) and (PD-L2/IDO-1) with worse OS (HR 1.98, p = 0.042, HR 1.92, p = 0.022). PD-L1/IDO-2 and PD-L2/IDO-1 co-expression high levels are independent negative prognostic factors for survival in early NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches.

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