Carboplatin plus pemetrexed for platinum-pretreated, advanced non-small cell lung cancer: a retrospective study with pharmacogenetic evaluation

Metro, Giulio; Chiari, Rita; Mare, Marzia; Giannarelli, Diana; Tofanetti, Francesca Romana; Minotti, Vincenzo; Ferraldeschi, M.; Giuffrida, Dario; Marcomigni, Luca; Bennati, Chiara; Fischer, Matthias; Meacci, M.; Bellavita, Rita; Pistola, Lorenza; Ludovini, Vienna; Crinò, Lucio

doi:10.1007/s00280-011-1632-x

Cited by 16 publications

(10 citation statements)

References 28 publications

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“…This SNP was not evaluated in a recent pharmacogenetic study in 73 NSCLC patients who had received salvage chemotherapy with the combination of carboplatin plus pemetrexed [25]. This study investigated SNPs at the XRCC3, XPD, ERCC1, GARFT, DHFR, and TS genes, but none of these SNPs was found to be a useful predictor of treatment efficacy.…”

Section: Discussionmentioning

confidence: 82%

Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed–carboplatin

et al. 2012

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Section: Discussionmentioning

confidence: 82%

Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed–carboplatin

et al. 2012

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“…29,30 Therefore, antisense-mediated enhancement of these drug combinations is desirable and potentially valuable therapeutically. Given that complementary lethality was separately induced to cross-linking agents and TS-targeting drugs by combined TS and BRCA2 siRNA treatment, we next determined whether combined complementary lethality to both types of drugs could be induced simultaneously in the same cell population and if the magnitude of drug potentiation could present a potential therapeutic benefit.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined “Complementary Lethality”

Rytelewski

Ferguson

Vareki

et al. 2013

Molecular Therapy - Nucleic Acids

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A high mutation rate leading to tumor cell heterogeneity is a driver of malignancy in human cancers. Paradoxically, however, genomic instability can also render tumors vulnerable to therapeutic attack. Thus, targeting DNA repair may induce an intolerable level of DNA damage in tumor cells. BRCA2 mediates homologous recombination repair, and BRCA2 polymorphisms increase cancer risk. However, tumors with BRCA2 mutations respond better to chemotherapy and are associated with improved patient prognosis. Thymidylate synthase (TS) is also involved in DNA maintenance and generates cellular thymidylate. We determined that antisense downregulation of BRCA2 synergistically potentiated drugs with mechanisms of action related to BRCA2 function (cisplatin, melphalan), a phenomenon we named “complementary lethality.” TS knockdown induced complementary lethality to TS-targeting drugs (5-FUdR and pemetrexed) but not DNA cross-linking agents. Combined targeting of BRCA2 and TS induced complementary lethality to both DNA-damaging and TS-targeting agents, thus creating multidrug sensitive tumors. In addition, we demonstrated for the first time that simultaneous downregulation of both targets induced combined complementary lethality to multiple mechanistically different drugs in the same cell population. In this study, we propose and define the concept of “complementary lethality” and show that actively targeting BRCA2 and TS is of potential therapeutic benefit in multidrug treatment of human tumors. This work has contributed to the development of a BRCA2-targeting antisense oligdeoxynucleotide (ASO) “BR-1” which we will test in vivo in combination with our TS-targeting ASO “SARI 83” and attempt early clinical trials in the future.

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“…Survival of advanced NSCLC and XRCC3 Thr241Met polymorphism was reported in 6 studies [11], [13]–[15], [30], but only 4 [11], [13]–[15] studies provided available data for meta-analysis. Indirect HR for OS was estimated from Kaplan-Meier curve in one study [11].…”

Section: Resultsmentioning

confidence: 99%

XRCC3 Thr241Met Polymorphism and Clinical Outcomes of NSCLC Patients Receiving Platinum-Based Chemotherapy: A Systematic Review and Meta-Analysis

Shen

et al. 2013

PLoS ONE

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IntroductionX-ray repair cross-complementing protein 3 (XRCC3) is an essential gene involved in the double-strand break repair pathway. Published evidence has shown controversial results about the relationship between XRCC3 Thr241Met polymorphism and clinical outcomes of non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy.MethodsA systematic review and meta-analysis was performed to evaluate the predictive value of XRCC3 Thr241Met polymorphism on clinical outcomes of advanced NSCLC receiving platinum-based chemotherapy. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were analyzed.ResultsA number of 11 eligible studies were identified according to the inclusion criteria. Carriers of the variant XRCC3 241Met allele were significantly associated with good response to platinum-based chemotherapy (ThrMet/MetMet vs. ThrThr: OR = 1.509, 95% CI: 1.099–2.072, Pheterogeneity = 0.618). The XRCC3 Thr241Met polymorphism was not associated with OS (MetMet vs. ThrThr, HR = 0.939, 95% CI:0.651–1.356, Pheterogeneity = 0.112) or PFS (MetMet vs. ThrThr, HR = 0.960, 95% CI: 0.539–1.710, Pheterogeneity = 0.198). Additionally, no evidence of publication bias was observed.ConclusionsThis systematic review and meta-analysis shows that carriers of the XRCC3 241Met allele are associated with good response to platinum-based chemotherapy in advanced NSCLC, while the XRCC3 Thr241Met polymorphism is not associated with OS or PFS.

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Carboplatin plus pemetrexed for platinum-pretreated, advanced non-small cell lung cancer: a retrospective study with pharmacogenetic evaluation

Abstract: In patients with platinum-pretreated, advanced NSCLC and favorable clinical prognostic factors, treatment with CBDCA/PMX is associated with a good clinical outcome and toxicity profile. None of the SNPs analyzed was found to be a useful predictor of treatment efficacy.

Cited by 16 publications

References 28 publications

Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed–carboplatin

Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed–carboplatin

Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined “Complementary Lethality”

XRCC3 Thr241Met Polymorphism and Clinical Outcomes of NSCLC Patients Receiving Platinum-Based Chemotherapy: A Systematic Review and Meta-Analysis

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