Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RRM1 is a gene crucial for determination of the tumor phenotype. It encodes the regulatory subunit of ribonucleotide reductase, and it is a molecular target of gemcitabine. In addition, RRM1 induces PTEN expression and inhibits cell migration, invasion, and metastasis formation. In patients with resected lung cancers, increased levels of RRM1 are highly associated with long survival. In contrast, patients on gemcitabine and cisplatin therapy for advanced disease have a poor survival if RRM1 expression is high presumably because of decreased efficacy of chemotherapy. We analyzed the RRM1 promoter for polymorphisms in an effort to develop a practical and inexpensive assay for RRM1 expression. Two single nucleotide polymorphisms, RR37 and RR524, were discovered. These polymorphisms impacted promoter activity in vitro and had different frequencies in various populations. Promoter allelotypes were highly associated with overall (P = 0.06) and disease-free (P = 0.03) patient survival. The allelotype with the highest predicted activity was associated with the best patient outcome. However, we did not find an association between allelotype and tumoral RRM1 expression. This is likely a result of the limited impact of the described promoter polymorphisms on overall in vivo gene expression. We conclude that clinical studies using RR37 and RR524 for decisions on chemotherapy are premature and that further functional studies on the RRM1 promoter are required to fully elucidate factors controlling RRM1 expression.
Lung Cancer 2005 Feb
PMID:Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance. 1563 17

Although no overall differences in survival have been observed between the many chemotherapy combinations in non-small-cell lung cancer, the clinical application of mRNA expression levels of amplified genes may disclose many genetic influences on cytotoxic drug sensitivity and enable clinicians to tailor chemotherapy according to each individual's gene profile. Specifically, the assessment of ribonucleotide reductase subunit M1 and thymidylate synthase mRNA expression levels might select patients who benefit from gemcitabine (Gemzar) or pemetrexed (Alimta) combinations. Until recently, clinical prognostic factors such as performance status, weight loss, and lactate dehydrogenase were the only parameters used to predict chemotherapy response and survival. However, accumulated data indicate that overexpression of genes involved in cancer glycolysis pathways plays an important role, and might be an independent mechanism of chemoresistance. The dysregulation of glycolytic genes is affected by growth signals involving the PI3K/Akt pathway and downstream genes such as hypoxia-inducible factor-1-alpha. One can thus envision that substantial improvements in therapeutic outcome could benefit from the integration of tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotide reductase antisense therapy, and targeted therapy.
 ...
PMID:The promise of pharmacogenomics: gemcitabine and pemetrexed. 1565 42

The pyrimidine analogue gemcitabine is an established effective agent in the treatment of non-small-cell lung cancer (NSCLC). The present study investigates whether gemcitabine would be synergistic with the topoisomerase I inhibitor topotecan against the NSCLC A549 and Calu-6 cells. Cells were treated with gemcitabine and topotecan for 1 h and the type of drug interaction was assessed using the combination index (CI). Cell cycle alterations were analysed by flow cytometry, while apoptosis was examined by the occurrence of DNA internucleosomal fragmentation, nuclear condensation and caspase-3 activation. Moreover, the possible involvement of the PI3K-Akt signalling pathway was investigated by the measurement of Akt phosphorylation. Finally, quantitative, real-time PCR (QRT-PCR) was used to study modulation of the gemcitabine-activating enzyme deoxycytidine kinase (dCK) and the cellular target enzyme ribonucleotide reductase (RR). In results, it was found that simultaneous and sequential topotecan --> gemcitabine treatments were synergistic, while the reverse sequence was antagonistic in both cell lines. DNA fragmentation, nuclear condensation and enhanced caspase-3 activity demonstrated that the drug combination markedly increased apoptosis in comparison with either single agent, while cell cycle analysis showed that topotecan increased cells in S phase. Furthermore, topotecan treatment significantly decreased the amount of the activated form of Akt, and enhanced the expression of dCK (+155.0 and +115.3% in A549 and Calu-6 cells, respectively), potentially facilitating gemcitabine activity. In conclusion, these results indicate that the combination of gemcitabine and topotecan displays schedule-dependent activity in vitro against NSCLC cells. The gemcitabine --> topotecan sequence is antagonistic while drug synergism is obtained with the simultaneous and the sequential topotecan --> gemcitabine combinations, which are associated with induction of decreased Akt phosphorylation and increased dCK expression.
 ...
PMID:Interaction between gemcitabine and topotecan in human non-small-cell lung cancer cells: effects on cell survival, cell cycle and pharmacogenetic profile. 1570 43

The treatment of advanced non-small-cell lung cancer (NSCLC is based on the combination of platin and one of the following agents: taxanes, gemcitabine, vinorelbine or irinotecan. There are no significant differences in efficacy among these combinations suggesting that the maximum efficacy has been reached. In this review, we will consider the mechanisms of chemoresistance of the five groups of cytotoxic drugs commonly used in the treatment of advanced NSCLC as well as the clinical studies which have assessed the value of chemoresistance markers. Breast Cancer Related Protein (BRCP) expression has been related to irinotecan and cisplatin (CDDP) resistance. DNA repair capacity influences response to CDDP and ERCC1 gene stands out as a predictive marker of CDDP sensitivity. Preliminary studies indicate that high tubulin III and stathmin mRNA levels correlate with response to paclitaxel and vinorelbine and that high expression of class III tubulin by tumor cells assessed immunohistochemically in patients receiving a taxane-based regimen is associated with a poor response to chemotherapy, and a shorter progression-free survival. High expression levels of ribonucleotide reductase has also been related to response to gemcitabine. Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) genotype has been reported to be associated with time to progression and survival in patients treated with irinotecan. These data suggest that pharmacogenomic strategies may be used for developing customized chemotherapy in prospective studies. Adjuvant chemotherapy which had recently shown its usefulness in limited lung cancer represents another area of investigation for pharmacogenomic studies.
 ...
PMID:Chemoresistance in non-small cell lung cancer. 1572 Feb 63

The nucleotide metabolism enzyme ribonucleotide reductase is composed of a regulatory subunit (RRM1) and a catalytic subunit (RRM2). The RRM1 locus has frequent loss of heterozygosity in lung cancers, ectopic expression of RRM1 suppresses proliferation of ras-transformed mouse fibroblasts, and high levels of RRM1 expression are associated with a significant survival benefit in patients with lung cancer. In RRM1 transgenic human lung and colon cancer cell lines, we observed induction of G(2) cell cycle arrest, apoptosis, and efficient DNA damage repair. We generated strains of RRM1 transgenic mice and found that carcinogen-induced lung tumor formation was significantly suppressed. The tumor suppression was more pronounced in strains with high levels of RRM1 expression than in those with low levels of expression. DNA damage repair capacity in transgenic animals was determined, and RRM1 transgenic animals repaired chemically induced DNA damage with greater efficiency than control animals. We conclude that the regulatory subunit of ribonucleotide reductase has tumor suppressor activity that is mediated through efficient DNA damage repair.
 ...
PMID:Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase. 1681 20

Five-year survival for non-small cell lung cancer is 15%. Gemcitabine is a nucleoside analogue that inhibits ribonucleotide reductase and interferes with DNA replication. In this study, we sought to compare short versus continuous infusion gemcitabine in an in vitro bioreactor system using pharmacokinetic-guided dosing. Gemcitabine was infused over either 0.5 or 2.5h to produce concentration-time profiles that mimic those measured in biological samples (i.e., patient plasma). The effects of gemcitabine on the growth and survival of H2009 cells were examined using trypan blue staining, cell cycle analysis, TUNEL assay, and clonogenic assay. Data were analyzed with two ways analysis of variance. Maximum gemcitabine (Cmax) concentrations during the short infusion were 51.2+/-10.4 microM and for the continuous, 14.8+/-2.93 microM. Steady-state concentrations during the continuous infusions were 14.9+/-2.90 microM. Gemcitabine treatment resulted in a decrease for G1 fraction relative to controls. G2/M, subG1 and TUNEL were higher following gemcitabine relative to controls. Survival was approximately 20-fold higher following the short infusion compared with the continuous infusion (p = 0.0085). In conclusion, gemcitabine infused by this novel method induced apoptosis after both the short and continuous infusions, and long-term survival was significantly diminished following continuous compared with the short infusion.
Lung Cancer 2007 Nov
PMID:Short versus continuous gemcitabine treatment of non-small cell lung cancer in an in vitro cell culture bioreactor system. 1765 59

The validation of predictive biomarkers to tailor chemotherapy is a key issue in the development of effective treatment modalities against cancer. Examples of how genetics might affect drug response are offered by gemcitabine. A substantial number of potential biomarkers for sensitivity or resistance to gemcitabine have been proposed, including ribonucleotide reductase and cytidine deaminase polymorphisms, human equilibrative transporter-1 and ribonucleotide reductase gene-expression and AKT phosphorylation status. These markers displayed a significant relationship with disease response to the drug; however, their robustness needs to be evaluated within prospective studies. Moreover, recent trials of customized chemotherapy based on genetic markers have been carried out in non-small-cell lung cancer and promising pharmacogenetic determinants are gaining momentum, including BRCA1 and ERCC1. Hopefully, biomarkers to select patients most likely to respond to gemcitabine will be validated in the near future.
 ...
PMID:Pharmacogenomics of gemcitabine in non-small-cell lung cancer and other solid tumors. 1910 17

Ribonucleotide reductase catalyzes the rate limiting step of deoxyribonucleotide formation, a crucially important step in DNA synthesis and repair. The regulatory subunit M1 of ribonucleotide reductase (RRM1) is the necessary part of the RR function and controls substrate specificity and global on/off enzyme activity. Despite recent research progress, the role of RRM1 in lung cancer sensitivity to chemotherapeutics remains to be elucidated. This study was to investigate the relationship between polymorphisms of the RRM1 gene and sensitivity to platinum-based chemotherapy in non-small cell lung cancer (NSCLC). Genomic DNA samples from 214 NSCLC patients treated with platinum-based chemotherapy were used to determine the RRM1 promoter allelotypes. The RR37CC-RR524TT was the most frequent allelotype (38.50%), followed by RR37AC-RR524CT (26.76%) and RR37CC-RR524CT (14.95%). The average response rate for chemotherapy was 44.4%. The response rates to the treatment regimens in the RR37CC-RR524TT, RR37AC-RR524CT and RR37CC-RR524CT allelotypes were 43.9%, 52.6%, and 51.6%, respectively. The response rates to therapy among patients with RRM1 (-)524 allelotypes were significantly different (p=0.046), whereas that among patients with RRM1 (-)37 allelotypes were not significant. Further analysis showed that the response rate in the patients with RR524CT allelotype (52.3%) was the highest, compared with that with RR37CC-RR524TT allelotype (43.9%, p=0.28), or the Others (RR524CC and RR37AC-RR524TT, 30.2%, p=0.02). Our results suggest that the RR524CT allelotype may be associated with an increased sensitivity to platinum-based chemotherapy in NSCLC. Further research on determining RR524CT as a clinical marker for predicting response to platinum-based therapy in NSCLC patients is warranted.
Lung Cancer 2009 Dec
PMID:Polymorphisms of the ribonucleotide reductase M1 gene and sensitivity to platin-based chemotherapy in non-small cell lung cancer. 1930 40

The p53-dependent RR small subunit (p53R2) protein, a newly identified member of the ribonucleotide reductase family, plays a key role in the p53-dependent cellular response to DNA. Several recent studies have suggested that p53R2 also plays an important role in suppressing the invasive potential of human cancer cells. However, the cellular mechanism that regulates invasiveness remains largely unknown. In this study, we show that p53R2 interacts with MEK2 (extracellular signal-regulated kinase (ERK) kinase 2-mitogen-activated protein kinase (MAPK) kinase 2), the molecule immediately upstream of ERK in the Ras-Raf-MAPK signaling cascade. In co-immunoprecipitation and immunofluorescence analyses, we found that p53R2 and MEK2 interact physically in cultured mammalian cells, and that the p53R2 segment comprising amino acids 161-206 is critical for this interaction. Moreover, serum-induced phosphorylation of MEK1/2 and ERK1/2 was greatly augmented in human cancer cells expressing small-interfering RNA against p53R2. On the other hand, phosphorylation of MEK1/2 and ERK1/2 in human cancer cells was markedly attenuated by overexpression of p53R2. Furthermore, MEK2 was required for p53R2 knockdown-induced enhancement of the invasive ability and anchorage-independent growth of human lung cancer H1299 cells. Taken together, these findings show that p53R2 negatively modulates serum-induced MEK-ERK activity and inhibits the MEK-ERK-mediated malignancy potential of human cancer cells.
 ...
PMID:Ribonucleotide reductase small subunit p53R2 suppresses MEK-ERK activity by binding to ERK kinase 2. 1939 49

We evaluated whether ribonucleotide reductase regulatory subunit M1 (RRM1) protein expression by immunohistochemistry (IHC) is a predictor of survival and response in gemcitabine-treated, advanced non-small cell lung cancer (NSCLC). We retrospectively collected 40 formalin-fixed, paraffin-embedded NSCLC tissues to investigate the protein expression of RRM1 by IHC with a purified rabbit anti-human RRM1 polyclonal antibody (ProteinTech Group, Chicago, IL, USA). RRM1 expression was positive in 14 (35%) and negative in 26 (65%) cases. Ten (25%) patients were treated as first-line and 30 (75%) patients as second-line. The median age was 61 years and M/F was 31/9. Stage IIIB/IV was 7/33 and adenocarcinoma/squamous cell carcinoma/other cell type was 20/16/4. Other characteristics, including age, gender, stage, cell type and first/second-line were not statistically different in the RRM-positive and RRM-negative groups. The overall survival of RRM1-positive groups was significantly shorter than RRM-negative groups (5.1 months vs. 12.9 months, p = 0.022). The response rates of 38 out of 40 patients were assessable. Disease control rate (PR+SD) of the RRM1-positive groups was significantly lower than that of RRM1-negative groups (23% vs. 56%, p = 0.053). In patients with gemcitabine-treated advanced NSCLC, patients with RRM1-positive tumors had worse overall survival and disease control than patients with RRM1-negative tumors.
Lung Cancer 2010 Nov
PMID:The immunohistochemical overexpression of ribonucleotide reductase regulatory subunit M1 (RRM1) protein is a predictor of shorter survival to gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). 2022 51


<< Previous 1 2 3 4 Next >>