RRM1 Modulated In Vitro and In Vivo Efficacy of Gemcitabine and Platinum in Non–Small-Cell Lung Cancer
ABSTRACT RRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low as opposed to high tumoral RRM1 expression when treated with gemcitabine-containing chemotherapy. However, the principal hypothesis that intratumoral levels of gene expression are associated with disease response has not been addressed.
We constructed genetically modified lung cancer cell lines with increased and decreased RRM1 expression to investigate the in vitro 50% inhibitory concentration (IC50) for gemcitabine, cisplatin, and carboplatin. A prospective phase II clinical trial in patients with locally advanced non-small-cell lung cancer was conducted with pretreatment tumor collection for determination of RRM1 and ERCC1 expression by real-time reverse transcriptase polymerase chain reaction. The levels of gene expression were correlated with tumor response after two cycles of gemcitabine and carboplatin.
In cell lines with a genetically engineered 15-fold RRM1 expression range, the gemcitabine IC50 had a 100-fold range, and the cisplatin and carboplatin IC50 had a two-fold range. They were highest in constructs with high RRM1 expression. In the prospective clinical trial, RRM1 expression was significantly (P = .002) and inversely correlated (r = -0.498) with disease response. ERCC1 expression showed a similar trend (P = .099).
The results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. ERCC1 expression is predictive of response albeit to a lesser degree.
- SourceAvailable from: Shuji Komori
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- "Because 5 -NT reduces phosphorylated metabolites of GEM, the activity level of 5 -NT might also be a target for evaluation as the one factor most affecting the clinical outcome of GEM chemotherapy . Although RRM1, dCK, and 5 -NT are useful predictors of GEM resistance , the individual actions of each of RR, dCK, and 5 -NT have not been reported as useful predictors of prognosis in pancreatic cancer chemotherapy . Namely, pancreatic cancer cells with a higher ratio of hENT1×dCK/RRM1×RRM2 showed higher cytotoxicity, and those cells with a lower ratio showed lower cytotoxicity . "
ABSTRACT: 5-fluorouracil (5-FU) is widely used in chemotherapy for gastric and colorectal cancer, but gemcitabine (GEM), and not 5-FU, is approved as a standard drug for use in pancreatic cancer. Interindividual variation in the enzyme activity of the GEM metabolic pathway can affect the extent of GEM metabolism and the efficacy of GEM chemotherapy. Human equilibrative nucleoside transporter 1 (hENT1) is recognized as a major transporter of GEM into cells. In addition, a factor that activates hENT1 is the inhibition of thymidylate synthase (TS), one of the 5-FU metabolic enzymes; TS inhibition mediates depleting intracellular nucleotide pools, resulting in the activation of the salvage pathway mediated through hENT1. In this paper, the role of 5-FU in GEM-based chemotherapy for pancreatic cancer is discussed with special emphasis on enzymes involved in the 5-FU and GEM metabolic pathways and in the correlation between GEM responsiveness and the expression of 5-FU and GEM metabolic enzymes.05/2011; 2011:936893. DOI:10.5402/2011/936893
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- "The ribonucleotide reductase regulatory subunit M1 (RRM1) may also contribute to cisplatin resistance when delivered in combination with gemcitabine  . However, although preclinical data suggests increased RRM1 expression levels are associated with resistance to cisplatin in vitro, the effect is less pronounced than that observed for gemcitabine . It may be that in this doublet combination the relationship to gemcitabine resistance is more clinically relevant in determining outcomes for patients. "
ABSTRACT: Management of patients with lung cancer continues to pose a considerable challenge to today's oncologist. While treatment may be curative in the early stages of the disease, the majority of patients are not diagnosed until the tumor has progressed beyond the primary site. Most patients face an intensive and invasive treatment regimen comprising surgery, radiotherapy, or chemotherapy, or combinations thereof depending on disease stage/performance status. Most will require chemotherapy even if their initial surgery is potentially curative; for those with advanced disease, chemotherapy may be their only treatment option. Moreover, the majority of patients will require multiple lines of therapy as their cancer cells acquire resistance to the chemotherapeutic agents to which they are exposed. Resistance to current chemotherapeutics available for the management of non-small cell lung cancer (NSCLC) represents one of the most significant barriers to improving long-term outcomes for this vulnerable patient group. Future management may lie in individualizing therapy through careful selection of appropriate agents based on the likelihood of response and the development of resistance. A number of biomarkers are emerging that predict response to current therapeutics; work is ongoing to develop appropriate algorithms based on such markers to guide treatment selection. In addition, novel chemotherapeutics are in development including new platinum analogs such as picoplatin (a cisplatin analog), ABT-751 (a sulfonamide) and tubulin binding agents (TBAs) such as the epothilones, providing hope for the future.Lung cancer (Amsterdam, Netherlands) 10/2010; 71(1):3-10. DOI:10.1016/j.lungcan.2010.08.022 · 3.74 Impact Factor
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- "Low level of human MutS homolog 2 (MSH2), a mismatch repair enzyme, was linked with sensitivity to cisplatin . Low expression of regulatory subunit of ribonucleotide reductase (RRM1) was associated with sensitivity to gemcitabine in cell lines as well as in a clinical setting . Low expression of BRCA1 seems to predict sensitivity to cisplatin , whereas high expression may be associated with sensitivity to antimicrotubule drugs such as taxanes and vinorelbine . "
ABSTRACT: Quantitative immunohistochemistry remains an important tool in translational lung cancer research with hopes to improve patient outcomes and avoid unnecessary therapies. Present review is aimed to summarize the use of immunohistochemical markers for improved prognostic information and prediction of treatment benefit. Several of these markers are currently explored in phase II-III clinical studies to individualize the treatment of lung cancer.Folia Histochemica et Cytobiologica 06/2010; 48(1):7-11. DOI:10.2478/v10042-010-0014-2 · 1.00 Impact Factor